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Alzheimer’s Disease: An Introduction to The Disease, its Mechanisms, and a Clinical Case Study

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A comprehensive research setup for monitoring Alzheimer’s disease using EEG, fNIRS, and Gait analysis

• Original Article
• Published: 09 August 2023
• Volume 14 , pages 13–21, ( 2024 )

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• Minhee Kim 1 ,
• Sehyeon Jang 2 ,
• Donjung Lee 3 ,
• Seungchan Lee 4 ,
• Jeonghwan Gwak 5 ,
• Sung Chan Jun 2 &
• Jae Gwan Kim   ORCID: orcid.org/0000-0002-1010-7712 1  

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Alzheimer’s disease (AD) has a detrimental impact on brain function, affecting various aspects such as cognition, memory, language, and motor skills. Previous research has dominantly used electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) to individually measure brain signals or combine the two methods to target specific brain functions. However, comprehending Alzheimer’s disease requires monitoring various brain functions rather than focusing on a single function. This paper presents a comprehensive research setup for a monitoring platform for AD. The platform incorporates a 32-channel dry electrode EEG, a custom-built four-channel fNIRS, and gait monitoring using a depth camera and pressure sensor. Various tasks are employed to target multiple brain functions. The paper introduced the detailed instrumentation of the fNIRS system, which measures the prefrontal cortex, outlines the experimental design targeting various brain functioning programmed in BCI2000 for visualizing EEG signals synchronized with experimental stimulation, and describes the gait monitoring hardware and software and protocol design. The ultimate goal of this platform is to develop an easy-to-perform brain and gait monitoring method for elderly individuals and patients with Alzheimer’s disease.

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Advancements in Measuring Cognition Using EEG and fNIRS

Emerging Non-invasive Brain–Computer Interface Technologies and Their Clinical Applications

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Acknowledgements

This work was supported by Brain Research Program, National Research Foundation of Korea (NRF-2016M3C7A1905475) and Healthcare AI Convergence Research & Development Program through the National IT Industry Promotion Agency of Korea (NIPA) funded by the Ministry of Science and ICT (No. S1601-20-1016)

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Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea

Minhee Kim & Jae Gwan Kim

School of Electrical Engineering and Computer Science, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea

Sehyeon Jang & Sung Chan Jun

Korea Photonics Technology Institute, Gwangju, 61007, Republic of Korea

Donjung Lee

Department of Medical Device, Korea Institute of Machinery & Materials, Daegu, 42994, Republic of Korea

Seungchan Lee

Department of Software, Korea National University of Transportation, Chungju, 27469, Republic of Korea

Jeonghwan Gwak

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Conceptualization: JGK, SCJ, JG; Methodology: MK, SJ, DL, SL; Formal analysis and investigation: MK, SJ; Writing–original draft preparation: MK; Writing—review and editing: MK, JGK; Funding acquisition: JGK, SCJ, JG; Supervision: JGK, SCJ.

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Correspondence to Jae Gwan Kim .

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Kim, M., Jang, S., Lee, D. et al. A comprehensive research setup for monitoring Alzheimer’s disease using EEG, fNIRS, and Gait analysis. Biomed. Eng. Lett. 14 , 13–21 (2024). https://doi.org/10.1007/s13534-023-00306-7

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Received : 03 April 2023

Revised : 10 June 2023

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Published : 09 August 2023

Issue Date : January 2024

DOI : https://doi.org/10.1007/s13534-023-00306-7

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Alzheimer’s Disease: An Overview of Major Hypotheses and Therapeutic Options in Nanotechnology

Mugdha agarwal.

1 Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201309, India; moc.liamg@1ahdgumlawraga

Mohammad Rizwan Alam

2 Department of Medical Genetics, School of Medicine, Keimyung University, Daegu 42601, Korea; moc.liamg@1002nawzirdm

Mohd Kabir Haider

3 Vellore Institute of Technology, Vellore 600127, India; moc.liamg@0002rediahribak

Md. Zubbair Malik

4 School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India

Dae-Kwang Kim

5 Hanvit Institute for Medical Genetics, Daegu 42601, Korea

Associated Data

All data have been illustrated in the manuscript.

Alzheimer’s disease (AD), a progressively fatal neurodegenerative disorder, is the most prominent form of dementia found today. Patients suffering from Alzheimer’s begin to show the signs and symptoms, like decline in memory and cognition, long after the cellular damage has been initiated in their brain. There are several hypothesis for the neurodegeneration process; however, the lack of availability of in vivo models makes the recapitulation of AD in humans impossible. Moreover, the drugs currently available in the market serve to alleviate the symptoms and there is no cure for the disease. There have been two major hurdles in the process of finding the same—the inefficiency in cracking the complexity of the disease pathogenesis and the inefficiency in delivery of drugs targeted for AD. This review discusses the different drugs that have been designed over the recent years and the drug delivery options in the field of nanotechnology that have been found most feasible in surpassing the blood–brain barrier (BBB) and reaching the brain.

1. Introduction

The most prevalent cause of dementia is Alzheimer’s disease (AD), a condition that affects approximately 50 million people worldwide, and the case of dementia is estimated to reach 131.5 million by the year 2050 [ 1 ]. AD is characterized by cognitive decline, behavioral change and inability to perform daily life activity [ 2 , 3 ]. Lack of successful Aβ clearance are thought to cause the onset or development of AD in most situations [ 4 , 5 , 6 , 7 ]. Available drugs that lower Aβ has been ineffective in preventing cognitive decline [ 8 , 9 , 10 ]. Despite continuous efforts by researchers towards finding a cure for the disease, more than a century since AD was first discovered, we have still been unable to come up with any significant treatment option, owing mainly to the lack of efficient drug delivery methods and several loopholes in the conventional drugs focusing on the symptomatic management of the disease and these drugs unlikely to stop the disease development [ 11 , 12 , 13 ].

Currently the FDA-approved drugs for AD in the market have limitations like high dosage regimes, low bioavailability, gastrointestinal tract side effects and ineffectual brain targeting, which ultimately lead to incompliance with the patient and discontinuation of the treatment [ 14 , 15 ]. This is where the role of nanotechnology comes into play. Advancements in this field have given rise to ease in the delivery of therapeutic molecules across the BBB and reaching the central nervous system (CNS) [ 16 ], along with the removal of other aforementioned impediments in the treatment process of AD.

2. Pathophysiology of the Disease

Alzheimer’s is characterized by the presence of amyloid beta plaques and neurofibrillary tangles that are formed in the patient’s brain [ 17 ]. Since the disease’s pathogenesis is multifactorial, the detection of behavioral and memory changes is difficult [ 18 , 19 ]. The mutations in three major genes encoding—amyloid precursor protein (APP) on chromosome 21, Presenilin-1 (PS1) on chromosome 14 and Presenilin-2 (PS2) are reported to be responsible for the formation of the same [ 20 ]. The mutations in these genes lead amyloid-β protein (Aβ) to form senile plaques in the extracellular region and the hyper phosphorylation of Tau protein that forms the neurofibrillary tangles intracellularly [ 21 ]. This causes widespread damage to nerve cells throughout the brain cortex, accompanied by early loss of cholinergic neurons from the basal region of the forebrain. There are a number of hypotheses that aid in the therapeutic formulation for AD and that have been discussed before. Some pharmacological treatments available for Alzheimer’s disease are shown in Table 1 .

Pharmacological treatments available for Alzheimer’s disease.

ER: Extended release, MOA: Mechanism of action, AChE: Acetylcholine esterase, NMDA: N-methyl-D-aspartate. Source: [NIH Publication, 2008, https://www.uspharmacist.com/article/alzheimers-disease-increasing-numbers-but-no-cure ].

2.1. The Amyloid-Beta Hypothesis

This hypothesis is the most recognized one amongst researchers, owing to its explanation for the senile plaque formation and the accumulation of Aβ oligomers as the major highlight of the disease [ 22 ]. The proteolysis of transmembrane protein APP by beta and gamma secretases forms single units of Aβ, which further undergo certain structural modifications to form sheets of oligomers that are harmful in nature. These oligomeric sheets aggregate to form plaques and tangles. The Aβ protein has two subunits—Aβ40 and Aβ42, where the latter is soluble. The APP is normally cleared by an enzyme called alpha secretase, which yields sAPP-alpha [ 23 , 24 , 25 ]. The sAPP-alpha is responsible for memory and learning activities of the brain, fighting against stress conditions and in maintaining neuronal excitability. In the diseased condition, the APP is cleaved by beta secretase into sAPP-beta and C99 fraction, which is membrane bound. Gamma secretase acts upon the C99 fraction producing either Aβ40 or Aβ42, which cause the plaques to deposit [ 26 , 27 , 28 ]. This disrupts the normal functioning of sAPP, leading to metabolic changes, decreased neuronal excitability, conditions favoring oxidative stress and dysregulated calcium homeostasis.

Recently, it has been discovered that APP cleavage occurs by a third way involving η-secretase [ 29 ]. The η-secretase is found to cleave APP at amino acids 504–505, which generates carboxy-terminal fragments Aη-α and Aη-β of higher molecular mass after undergoing a second cleavage by α-and β-secretase, respectively. An Aβ (1–16) fragment is contained by the Aη-α sequence, which is found to be neurotoxic. Aβ plays a role in memory and synaptic plasticity, although its proper function in the brain remains unknown yet [ 30 ]. AD has two main forms: A late-onset form known as sporadic AD, which is more common; and an early-onset or familial form with 5% of all AD cases [ 31 ]. It has been seen that in individuals suffering with Down’s syndrome (or trisomy 21), there is an increased risk of familial AD, as they are carriers of an extra chromosome 21 where the gene responsible for the formation of APP is present ( Figure 1 ).

Amyloid precursor protein (APP) cleavage in normal (non-amyloidogenic) and AD (amyloidogenic) pathways.

Similarly, a mutation in some of the many genes including PSEN1 and PSEN2, which code for APP, Presenilin1 and Presenilin2 which are also the two subunits of γ-secretase, have been recognized as the causative genes for familial AD [ 20 ]. These mutations cause an enhanced production of Aβ, with the mutations on PSEN1 particularly leading to an increase in formation of Aβ (1–42). The apolipoprotein (ApoE), which is involved in the clearance of Aβ, is a major genetic risk factor associated with late-onset AD [ 32 , 33 ]. There are three categories in which the mutations have been divided: The N-term mutation occurring at the cleavage site for β-secretase, the C-term mutation at the cleavage site for γ-secretase, and the mutation occurring in the mid-domain Aβ region. The mutations that occur at γ-secretase cleavage site can increase the ratio of Aβ1–42/Aβ1–40 and alter the position of cleavage. There is an increase in the rate of proteolysis of APP by β-secretase due to the mutations at β-secretase cleavage site. While the mutations occurring at the mid-domain of Aβ region in APP lead to an increase in the Aβ propensity for formation of oligomers and fibrils that disrupt the Aβ assembly. Many studies have reported mutation at the γ-secretase processing site of APP [ 34 , 35 , 36 , 37 , 38 ]. More than the protofibrils and fibrils, it is the oligomers that are found to be more toxic for the brain cells ( Figure 1 ). This is because the oligomers are capable of permeating the cellular membranes causing cellular dysfunction and death.

The cascade of Aβ involves a number of factors and modulators that have an essential role each to play. Metal ions such as iron, zinc and copper are found to be present in the amyloid plaques and are involved in creating conditions of oxidative stress, as well as in the modulation of aggregation process by binding to Aβ [ 39 ]. These ions function by acting on the kinetics or thermodynamics to affect the structural morphology of the aggregates formed. The amyloid aggregates that have metal ions entrapped within them have been found to be highly toxic as they can cause the production of reactive oxygen species (ROS) which have a deleterious effect on both the Aβ peptide and the biomolecules in the vicinity [ 40 ]. Release of inflammatory factors like reactive oxygen species (ROS), nitric oxide synthase (NOS) and prostaglandins is stimulated bringing about the death of nerve cells [ 41 ].

There are drugs that serve as beta and gamma secretase inhibitors, including Elenbecestat (E2609), verubecestat (MK-8931) and Semagacestat [ 42 ], but none of them have cleared all the steps of clinical trials [ 43 ]. Similarly, beta secretase modulators also failed due to their unsafe use to patients. The cleavage of APP by α- and γ-secretase produces sAPPα (soluble amino terminal ectodomain of APP), a larger C83 fragment (carboxy terminal) and a smaller fragment p3. This pathway does not give rise to amyloid beta (Aβ) production. The cleavage of APP by β-secretase (BACE1) and γ-secretase produces sAPPβ, C99, AICD (APP intracellular domain) and leads to the formation of Aβ [ 44 , 45 ].

2.2. The Tau Hypothesis

Tau is present in axons and dendrites and it regulate microtubules function [ 46 , 47 , 48 , 49 ]. The biological functioning of Tau is regulated by the level of its phosphorylation in the brain. Tau generally contain 2–3 mole of phosphates per mole of protein, but, in the case of AD brain, it contains more phosphates [ 50 , 51 ]. An excessive or hyper phosphorylation of microtubule-associated protein, Tau in case of AD, leads to its transformation from normal adult Tau to a paired helical filament (PHF-tau) of it, impairing its ability to bind to the microtubules stably [ 52 , 53 ]. This is a result of mutations that cause tau to aggregate and attain an insoluble structure, as opposed to their normal soluble structure. The insoluble state leads to enormous destruction of cytoplasmic functions of the nerve cells and a disruption in axonal transport, ultimately leading to dementia and neuronal death [ 54 ]. Neuronal cell death mediated by tau along with hyperphosphorylation also requires the activation of glycogen synthase kinase 3β (GSK3-β). Previous studies have reported that inhibition of GSK3-β decreases tau phosphorylation [ 55 , 56 ] ( Figure 2 ). The tau pathology states that the formation of neurofibrillary tangle (NFT) spreads to various parts of the brain by following a stereotyped pattern of six pathological stages, wherein the first two stages the cognition of the patients is impaired.

Interactions occurring between amyloid beta (Aβ), hyperphosphorylated tau, glycogen synthase kinase 3β (GSK-3β) and ceramides (cer).

There is a neurodegenerative “triad” of cellular changes that has been revealed via the microscopic analysis of different models of AD animals as well as AD patients, which affects the disease development. This triad comprises of: (a) A density decrease accompanied by a change of shape of the dendritic spines, which are the postsynaptic excitatory input site of most neurons; (b) neuronal cell loss in specific regions of the brain; and (c) a subset of neurons that undergo dendritic simplification. Over the years, the emergence of different events of the neurodegenerative triad may occur at different points of time with the progression of AD [ 57 ]. Studies on organotypic cultures and animal models have shown that the loss of dendritic spines and changes in synapse begin to surface very early in the disease. These changes; however, can be reversed if the amount of Aβ is reduced and the cAMP/PKA/CREB signaling pathways are restored [ 58 ] ( Figure 2 ).

Loss of neurons and dendritic simplification are events that are found to appear later in the disease, which suggests that the aspects of neurodegenerative triad dependent on tau are characteristic of further disease progression. It is clear that the loss of neurons is an irreversible event, the reversibility of dendritic simplification; however, is yet to be established. Since it is known that the loss of synapse and dendritic simplification is caused due to a disruption of the cytoskeleton, drugs capable of modulating dynamics of the cytoskeleton, and the microtubular network dynamicity in particular, can serve as therapeutic options for the counteraction of tau-mediated changes [ 59 ]. In tau knockout animal models, it was observed that there was no major effect on the development and function of brain. This led to an increased interest in the development of such strategies that were directed to tau, as they would have fewer side effects as compared to the drugs that were directed on APP and Aβ, which are involved in numerous biological processes. There are six isoforms of tau present in the CNS that are produced by the alternative splicing of three axons [ 60 , 61 ]. Any error in the splicing of tau, particularly an increased formation of longer isoforms of tau can lead to tauopathies. PHF-tau is phosphorylated at its serine and threonine residues several times [ 62 , 63 , 64 , 65 ].

Tau undergoes a number of post-translational modifications such as ubiquitination, acetylation, methylation and O-glycosylation. Studies on mouse models have shown that tau turnover was reduced and tau aggregation was increased through the acetylation of tau at Lys174, which was identified as an early modification in the brains of AD patients [ 66 ]. A number of interaction partners of tau that could be of functional importance have been found apart from microtubules, such as annexin A2, a membrane associated protein contributing to the axonal localization of tau; fyn, a non-receptor tyrosine kinase of the src-family involved in post-synaptic Aβ toxicity; and a primary tau phosphatase, protein phosphatase 2A.

GSK-3β is the major kinase involved the phosphorylation process of tau. With the aid of GSK-3β, the intracellular aggregation of Aβ occurs that might also contribute to the hyperphosphorylation of tau. Additionally, the Aβ aggregation acts on sphingomyelinases (SM; enzymes involved in the degradation of sphingomyelin) affecting ceramide production. The ceramides produced act on β-secretase (enzyme involved in proteolytic cleavage of APP) leading to increased Aβ production. Presenilin and brain-derived neurotrophic factor (BDNF) are responsible for modulating these interactions by the P13-K/Akt signaling pathway. P13-K causes activation of the Akt/protein kinase B, which further causes phosphorylation of GSK-3β inducing its inactivation and; thus, downregulating phosphorylation of tau.

2.3. The Cholinergic Hypothesis

It is the oldest known hypothesis which forms the basis of most of the drugs available in the market today [ 67 ]. According to this hypothesis, there is a reduced rate of production and transportation of the neurotransmitter acetylcholine in the brains of AD-affected individuals [ 68 ]. This neurotransmitter is used by all the cholinergic nerve cells and has an important role in the peripheral and central nervous systems, as it is used by all pre and post-ganglionic parasympathetic nerve cells and also all the pre-ganglionic sympathetic nerve cells. Studies have shown that the cholinergic system is a crucial contributor to the learning and memory processes [ 69 , 70 , 71 , 72 , 73 ]. In AD, the cholinergic neurons forming the nucleus basalis of Meynert are specifically degenerated, which causes memory loss seen in the AD patients [ 74 , 75 , 76 , 77 , 78 ]. The nucleus basalis region of a healthy adult brain contains about 500,000 cholinergic neurons, whereas a mere 100,000 remain in advanced AD patients [ 79 ]. There is a major decrease in the transcription of enzyme choline acetyltransferase (ChAT) in the remaining cholinergic nerve cells, leading to diminished activity of ChAT and the condition of dementia. It has also been found that the release of ACh in the forebrain can be regulated by stress conditions. A disruption in its transmission process is capable of affecting all aspects of cognition, the cortical and hippocampal information processing and behavior. Any change from the normal in the cholinergic inputs to the brain cortex leads to an impairment in attention and cognitive functions such as the processing of instructions required for decision making.

Moreover, it has been found that memory and knowledge encoding is impaired upon the blockage of CA3 cholinergic receptors. A reduction in the cholinergic neurons and the resulting impaired dopaminergic transmission has also been considered as a major factor related to psychiatric symptoms in AD. This hypothesis can be supported by the fact that there is an increase in the efflux of dopamine in nucleus accumbens as seen in M4 knockout mice. The loss of cholinergic neurons is not only found in the case of AD, but also in a number of other neurodegenerative disorders including PD, HD and ALS where a significant decrease in the activity of ChAT is seen [ 80 ]. The cholinergic synapses are severely affected by Aβ, which can be correlated to the cognitive decline. The hippocampal synaptic transmission is changed with respect to changes in the expression of synaptophysin, a major presynaptic vesicle protein p38, which correlates highly with the neuropathology and memory loss observed in AD patients. A severe deficit in basal synaptic transmission (~40%) was recorded upon electrophysiological studies in the hippocampal region of mutant APP mice.

Cholinergic neurons play a significant role in promoting memory and cognitive functions, as proven via experimentation studies on rat models using cholinergic antagonists which showed cognitive damage in the rats [ 81 , 82 ]. The coupling of M1 muscarinic receptors to G-proteins is damaged in the neocortex of AD patients. It has been demonstrated that the extent of this uncoupling of M1 and G-protein is linked to the graveness of cognitive symptoms in AD. Further, a shift in the processing of APP towards the non-amyloidogenic pathway occurs when muscarinic receptors are activated. M1 receptor signaling is also known to be affecting a number of hallmarks in AD, such as cholinergic deficiency, Aβ and tau pathologies and cognitive dysfunctions. M1 receptor activation can activate PKC and inhibit GSK3-β, which can lead to a significant reduction in tau hyperphosphorylation. AF267B, a known M1 agonist, is capable of rescuing the decline in cognition via a decrease in Aβ42 and abnormalities associated with tau in the cortex and hippocampus, as seen in an AD mouse model. These findings and several other studies have produced the option of M1 acetylcholine receptor agonists as potential therapeutic tools for treating AD. Acetylcholinesterase (AChE) inhibitors, like Donepezil, work by decreasing the hydrolysis of Ach and improving memory and cognition [ 83 ], while Rivastigmine serves an additional function of blocking not only acetylcholinesterase, but also butyl cholinesterase to increase the chances of managing AD ( Figure 3 ). Similarly, there is Galantamine which is an effective drug working as an AChE inhibitor on the same mechanism.

A diagrammatic representation of the neuroprotective activity of Acetylcholine esterase (AChE) inhibitors (such as Donepezil and Galantamine).

They stimulate nAchr (nicotinic acetylcholinesterase receptor) through a site other than the AChE binding site under normal condition. α7 nAChR, when stimulated by these drugs, causes the activation of PI3K (phosphatidylinositol 3-kinase) due to the activation and association of Jak2 (janus activated kinase 2) with the non-receptor type tyrosine kinase Fyn. Activation of PI3K activates Akt by phosphorylation (Akt-p). Nicotine treatment increases the level of Akt-p. It further increases the Bcl-2 expression level, preventing the death of nerve cells. The hypoactivation of α7 nAChR decreases activation of PI3K and Jak2. This increases GSK-3β enzyme activity, which increases phosphorylation of tau proteins causing neuronal death [ 84 ].

2.4. The Dendritic Hypothesis

This hypothesis focusses on the degeneration of dendrites accompanied with their structural and functional disturbances caused in AD. The activation of N-methyl-d-aspartate receptor (NMDAR) finds a major implication in Alzheimer’s disease, which has been studied extensively over the last few years. NMDARs are crucial for the processes of neurotransmission and synaptic plasticity in the brain [ 85 , 86 , 87 , 88 ]. Glutamate is the most abundantly present excitatory neurotransmitter found in the mammalian CNS. Ligand-gated ionotropic glutamate receptors (iGluRs) play a pivotal role in the excitatory neurotransmission, and a disruption in their normal signaling process is associated with a number of neuropathological diseases like AD, PD, HD and multiple sclerosis, which makes them important therapeutic drug targets [ 89 , 90 ]. There are three subfamilies of iGluRs, which are: a-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptors (AMPARs), kainate receptors and NMDARs. Owing to certain unique properties associated with it, the NMDAR is distinct from the other two iGluRs in the voltage-dependent activation [ 90 , 91 ]. The NMDAR has high permeability to calcium ions (Ca2+) and its ligand-gated kinetics is relatively slow, which makes it crucial in synaptic functions. The Ca2+ channel of NMDAR remains blocked by Mg2+ at the resting membrane potential (−70 mV), while this blockade is removed during the long term potentiation (LTP), allowing a prolonged and strong release of glutamate from the presynaptic terminal [ 92 , 93 ]. This leads to the activation of AMPARs and subsequently the depolarization causes Mg2+ removal from the NMDAR channel and a Ca2+ influx. This also triggers the activation of a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated signaling cascade, which causes an increase in the synaptic strength. A moderate activation of NMDARs causes a moderated increase in the postsynaptic Ca2+ and a trigger of phosphatases mediating long term depression (LTD) [ 94 ].

There are two types of membrane NMDARs: Synaptic and extrasynaptic. By the activation Ca2+ dependent transcription factors, such as cyclic-AMP response element binding protein (CREB) and the suppression of apoptotic pathway and caspases, the synaptic NMDAR helps in promoting the expression of survival gene [ 95 ]. The extrasynaptic NMDAR, on the contrary, is involved in glutamate excitotoxicity and cell death. Its responses are strongly linked with the physiological changes in AD. The activation of the two NMDARs occurs by two different endogenous coagonists: D-serine for synaptic NMDAR and glycine for extrasynaptic NMDAR. The signaling pathway mediated by extrasynaptic NMDAR is known to antagonize the cell survival pathway via CREB inactivation and FOXO (forkhead box) transcription factor activation which promotes pro-apoptotic and oxidative stress signaling [ 96 ]. AD affects the NMDAR coagonist levels. As the binding of coagonist D-serine or glycine is needed for the complete activation of NMDARs by glutamate, the coagonists serve an essential modulatory role in the functioning of NMDAR. One of the FDA approved drugs for AD, memantine, works as an NMDAR antagonist and targets against the extrasynaptic NMDAR. The level of Ca2+ entering through NMDAR that exceeds the pathological normal [ 97 ] determines the level of toxicity produced. It results in a gradual loss of synaptic plasticity and neuronal death eventually that can be clinically correlated to a decline in memory and cognition in AD patients. Not only is the electrophysiological functioning of NMDARs directly modulated by Aβ, an elevation in the levels of synaptic currents and collateral toxicity mediated by NMDARs is also brought about by Aβ in AD. NMDAR antagonists such as MK-801 serve as the blockers or attenuators of the same.

Since NMDARs also play an essential role in cell survival, a balance in their level of signaling is of utmost importance, such that it is sufficient for neuronal survival and at the same time, does not bring about neurodegeneration as in the case of AD [ 98 ]. The amount of glutamate available for signaling depends upon its uptake and recycling system, which was found to be severely compromised in AD. A study on an AD patient revealed that there is severe reduction in the capacity of glutamate transporter and protein expression [ 99 ]. The expression of presynaptic proteins, including syntaxin and synaptotagmin, which comprise the neurotransmitter release machinery, are known to be greatly reduced due to Aβ. Aβ can interact with NMDARs indirectly via such synaptic proteins as PSD95 [ 100 ]. The deficiency in presynaptic proteins leads to a compromised availability of glutamate, thus producing excitotoxicity, an effect often seen in degenerating nerve cells. The activation of N-methyl-D-aspartate (NMDA) receptor by the amyloid beta and prion proteins, in addition to the activation of Fyn by prion protein and Fyn tyrosine kinase-metabotropic glutamate receptor 5 complex (FynmGluR5), results in the decrease of NMDA receptors [ 101 ]. Fyn, upon overstimulation, causes cognitive damage and synaptic losses leading to the disease condition [ 28 ]. Memantine, a drug that functions as an NMDA receptor blocker, has been approved by FDA and is currently in use, although relatively preferred less in comparison to AChE inhibitor drugs.

2.4.1. Wnt/Beta-Catenin Signaling

The low density lipoprotein receptor-related protein 6 (LRP6) is a major Wnt co-receptor required to activate the Wnt/β-catenin pathway on the cell surface. LRP6 is strongly related to the signaling pathway of glucose and lipid metabolism [ 102 , 103 , 104 ]. The Wnt/β-catenin pathway is responsible for the regulation of a number of significant cellular functions, such as cell growth and proliferation, differentiation and migration. A dysregulation in this pathway has been found to play an important role in AD pathogenesis. The pathway is activated when Wnt proteins bind to the Frizzled (Fzd) receptor family’s cysteine rich domain and Wnt co-receptor LRP6. Studies have shown that susceptibility of neurons to death induced by amyloid beta increases with a decrease in the Wnt/β-catenin signaling, whereas the same Aβ-induced neuronal death can be prevented by the activation of this signaling [ 105 , 106 ]. Whether there is occurrence of neurogenesis in an adult human brain has been a much debated topic. There is evidence supporting the occurrence of neurogenesis in the hippocampal region of the human brain which experiences a sharp decline in the case of AD.

Studies show that the Wnt/β-catenin signaling has a key role in the regulation of neurogenesis in adult hippocampus, as it is activated by the Wnt7a gene at multiple steps of neurogenesis along with other specific genes controlling the neuronal cell cycle and differentiation processes [ 105 , 107 ]. It was found that, in aged mice, the Wnt proteins secreted by astrocytes decrease, causing decreased Wnt/β-catenin signaling, decrease in the level of survivin (responsible for mitotic regulation) in neural progenitor cells (NPC) and an impaired neurogenesis [ 108 ]. The activation of the Wnt/β-catenin signaling pathway determines the activation of survivin and transcription factors, such as NeuroD1 and Prox1, which are involved in the generation of hippocampal granule cells [ 109 ]. Furthermore, this signaling pathway plays an essential role in maintaining the synaptic plasticity. The Wnt proteins are involved in synapse formation and the pre- and post-synaptic modulation of neurotransmission. LRP6 helps in the in vivo and in vitro development of excitatory synapse and its deficiency leads to abnormal synapse and cognition, as found in aged mice models [ 107 , 110 ]. Other functions associated with the activation of LRP6-mediated Wnt/β-catenin pathway include the function and formation of blood–brain barrier (BBB), by activating the signaling in endothelial cells of the BBB, and inhibition of β-plaque formation via inhibition of transcriptional expression of β-site APP cleaving enzyme (BACE1) [ 111 , 112 , 113 , 114 ]. Interaction of LRP6 with APP lowers the production Aβ and the suppression of tau phosphorylation via suppression of the GSK3β kinase activity.

2.4.2. GSK3-β Activity

Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase that functions as a key regulator in many biological pathways, some of which have their implications in AD. It has two isoforms, GSK3-α and GSK3-β, each encoded by a different gene. The GSK3-β is found in abundance in the CNS, with the level of its expression increasing with age, and its activity superseding the normal in case of AD patients [ 56 ]. The over activation of this kinase is linked with the deposition of amyloid beta, memory impairment and plaque-related inflammatory responses mediated by microglia. The cleavage of APP in the non-amyloidogenic pathway that involves α- and γ-secretases has three members ofthe α-disintegrin and metalloproteinase (ADAM) family (ADAM-10, ADAM-17, and ADAM-9) forming the α-secretase complex [ 113 , 115 ]. GSK3-β is known to inhibit the activity of ADAM and thus downregulate the activity of α-secretase complex. Amongst the proteins constituting the γ-secretase complex, the function of presenilin (PSEN) 1 is affected by GSK3-β [ 116 ]. Since APP and PSEN1 are both substrates of GSK3-β, it interferes with the production of Aβ at the step of APP cleavage by γ-secretase [ 117 ].

The signaling of this kinase is found to be activated by Aβ, as its inhibition via phosphorylation is prevented by Aβ in transgenic AD models of animals. Similarly, an increased GSK3-β activity was observed in the brains of AD patients. A reduction in Aβ production, as well as Aβ-induced neuronal toxicity, was seen upon the inhibition of GSK3-β in mice models of AD. BACE1 mediates the APP cleavage by NF-kB signaling mechanism [ 112 , 113 , 114 ]. The expression of BACE1, which is found to be increased in AD patients, can be downregulated upon GSK3-β inhibition [ 112 ]. GSK3-β is known to phosphorylate at least 36 different residues in the tau protein, with the major sites identified to be Ser199, Thr231, Ser396, Ser413 and other sites of moderate phosphorylation including Ser46 and Ser202/Thr205 [ 118 , 119 , 120 ]. Apart from GSK3-β, CDK-5 and PKA are two other kinases associated with microtubules and tau protein. Tau is a microtubule-associated protein (MAP) that functions as a regulator of microtubule formation and its stability [ 121 , 122 ]. A combined action of GSK3-β and CDK-5 is required for the formation of paired helical filaments of tau (PHF tau) [ 123 ]. This form of the tau protein is insoluble and can aggregate and deposit inside the nerve cells leading to the formation of neurofibrillary tangles (NFTs). The PHF tau is unaffected by the action of proteases or phosphatases. Studies have shown that GSK3-β is activated by an elevation in oxidative stress, neuroinflammation and apoptotic cell death that is brought about by hyperphosphorylated tau [ 117 ]. Along with neuronal death and hyperphosphorylation in tau, GSK3-β overexpression has been found to cause a failure in mice to perform the Morris water maize test [ 124 ]. It causes increased apoptosis in some particular areas of the brain, including the hippocampus which controls memory and cognition and is severely affected in AD. However, it was seen that these effects were reversed and tau hyperphosphorylation was reduced upon restoration of GSK3-β to the normal levels. GSK3-β can regulate the stability of axons directly by interacting with microtubules, owing to its capacity to phosphorylate numerous MAPs [ 125 ].

The MAP-2 and tau phosphorylated by GSK3-β are deprived of their affinity towards microtubules, making them unstable in nature. Failure in axonal transport results, which adds significantly to the pathology of AD [ 125 ]. GSK3-β is known to be involved in the metabolism of choline and regulation of choline acetyltransferase (ChAT), as well as acetylcholinesterase [ 126 ]. A reduction in phosphorylation of Ser9 of GSK3-β has shown to cause a loss of cholinergic nerve cells from the basal forebrain and hippocampal area, and an enhanced phosphorylation of tau [ 118 , 119 , 120 ]. GSK3-β plays an important role in the process of inflammation, as it can regulate the process in a positive manner by promoting the activity of pro-inflammatory cytokines [ 127 ], while lowering anti inflammatory cytokines activity. Over the recent years, a number of GSK3-β inhibitors have been developed, both ATP-and non-ATP-competitive types [ 128 ]. Since the non-ATP-competitive GSK3-β inhibitors prove to be more sensitive, selective and less toxic in nature, they are preferred more than the ATP-competitive type (Indirubin).

2.5. The 5-HT 6 Receptor Hypothesis

It has been found in recent studies that the inhibition of antagonists at serotonin type 6 (5-HT 6 ) receptor can improve cognition in AD [ 129 , 130 , 131 , 132 ]. The injection of 5-HT 6 receptor antagonists in rodent models led to significant cognitive improvement [ 133 , 134 ]. This receptor is also found to be involved in amyloid protein formation and the signaling of Fyn [ 135 ]. These receptors can; therefore, play a major role in AD treatment as the inhibitors can also stop Fyn activation and deposition of amyloid. All the current drugs, apart from AChE inhibitors, have adverse effects associated with them which fails them in phase 2 or 3 of clinical trials [ 136 ]. It is worth noting that Dimebon (latrepirdine, also known as Dimebolin) was initially developed as an antihistamine drug. For 5-HT 6 receptors (ki = 34 nM), this compound shows strong affinity. After a very promising phase 2 review, Dimebon gained widespread attention as a possible treatment for AD [ 137 ]. A more recent multinational phase 3 research; however, has shown no changes [ 138 ].

3. Nanotechnology-Assisted Drug Delivery Strategies for AD

All the drugs currently approved for the treatment of AD are available as oral formulations, barring Rivastigmine which also has a transdermal patch available [ 28 , 139 ]. Since the drugs need to reach the CNS in order to control the progression of disease or its symptoms, a much higher dose needs to be consumed because of the large fraction of drug that is lost along the way in GI tract and metabolism in the hepatic region [ 28 , 139 ]. Furthermore, the drug needs to bind to serum albumin in the blood stream in order to sustain a decent half-life, before it finally reaches the BBB [ 140 , 141 ]. Consuming these dosages leads to the patients suffering with side effects like nausea and diarrhea and reducing their compatibility. Nanotechnological advancements in the recent years have provided us with the option of nanoparticles that help in overcoming these hurdles in drug delivery, particularly in improving the side effects by reducing the dosage and in easily traversing across the BBB to provide targeted delivery of the drug. The size of nanoparticles falls in the range of 1 to 100 nm so as to permeate the BBB [ 140 , 141 ].

They are formulated in such way that makes them nontoxic, biodegradable and target-specific in nature. These types of nanosystems may effectively hold and distribute drugs and other neuroprotective molecules to the brain in the sense of treating AD [ 142 , 143 , 144 ]. The intranasal route plays a role in overcoming the BBB and targeting the drugs directly to the brain [ 145 , 146 , 147 , 148 , 149 ]. However, in order to optimize pharmacotherapy in patients with AD, nasal, dermal, and intravenous routes may be used to administer nanodevices to target the brain moving through BBB to improve bioavailability, pharmacodynamic properties and decrease the adverse effects of these medications [ 150 , 151 , 152 ]. The most common mechanisms of nanoparticle transportation include endocytosis, like receptor-mediated endocytosis, phagocytosis and pinocytosis, with receptor-mediated endocytosis being the most preferred method. The incorporated drug is delivered at the target site by diffusion and erosion or degradation processes. Some of the nanoparticles most often used are liposomes, polymeric nanoparticles, micro- and nanoemulsions and dendrimers.

3.1. Liposomes

These are bilayered phospholipids that are amphiphilic in nature (i.e., capable of transporting both hydrophilic and lipophilic drug molecules) [ 153 , 154 ]. Some antibodies have been proposed to inhibit the spread of Tau pathology by microglial phagocytosis of the antibody–Tau complex and to promote the clearance of lysosomal Tau in neurons after endosomal uptake [ 155 , 156 ]. The main components of liposomes include phosphatidyl choline, sphingomyelin and glycerophospholipids. Liposomes contain cholesterol that helps in maintaining its stability inside the serum. Their size ranges typically from 50 to 100 μm. The drug is encapsulated inside a lipid bubble which aids in its protection from degradation by enzymes and retains its effectiveness [ 157 ]. Liposomes have been studied by researchers extensively over the years.

3.2. Polymeric Nanoparticles

These are nanoparticles composed of synthetic or natural polymers, having their size in the range 1–100 nm [ 158 ]. The hydrophilic or hydrophobic nature of PNPs depends on the nature of the part forming its outermost layer. The mechanism of their transport to the target site can either be via receptor-mediated endocytosis or transcytosis of endothelial cells. The absorption of drugs can be enhanced by coating the PNPs with antibodies or PEG (polyethylene glycol), especially while delivering the drug via the intranasal route. Poly (n-butyl cyanoacrylate) loaded with the drug Rivastigmine showed improved drug delivery in case of AD when coated with polysorbate-80 [ 28 ]. In an experimental AD model, Aβ1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leads to complete correction of the memory defect [ 159 ]. With unique quantum properties that are promising to diagnostic and imaging purposes, nanoparticles can be prepared [ 160 ]. Micelles, nanogels, dendrimers and nanocapsules can be formulated as polymeric NPs [ 161 , 162 ].

3.3. Micro- and Nanoemulsions

These types of nanoparticles fall under the category of surfactant-based systems. The size of microemulsions ranges between 10 to 140 nm, while that of nanoemulsions lies around 100 nm [ 163 ]. These systems are also called oil-in-water (O/W) heterogeneous systems as they are formed by the dispersion of oil in water or any other aqueous medium. Hyaluronic acid-based nanoemulsion of curcumin and resveratrol used by Nasr showed promising results when delivered via the intranasal route to the brain. The preparation of the nanoemulsion was done using spontaneous emulsification method [ 139 ]. As a possible carrier of memantine for a direct nose-to-brain transmission, the produced nanoemulsion could be used [ 164 ].

3.4. Dendrimers

These are polymeric branched, globular molecules also known as cascade molecules or arborols. They derive their name from their structural nature, which is to ramify progressively while originating from a core, similar to the behavior of the branches of a tree. Divergent and convergent are two methods of production of dendrimers. They offer a high drug loading capacity, including both the inner cavity and the outer surface of the dendrimer. The size of dendrimers can be easily regulated through careful selection of the monomers and the degree of polymerization. The only limitation is the issue of toxicity that is often faced when using these nanoparticles shown in Figure 4 .

Diagrammatic representation of drug delivery options using nanotechnology for therapeutic purposes in AD.

Polyamidoamines (PAMAMs), which are biocompatible, nonimmunogenic, and hydrophilic in nature, are the most used dendrimers in drug delivery. The nucleus of these dendrimers was composed of branching hydrophobic molecules of ethylenediamine and methylacrylate terminated by groups of carboxyl and amine. PAMAM dendrimers are used in drug delivery as carriers [ 165 ], diagnostic agents [ 166 ], gene transfection [ 167 ] and boron neutron capture treatment for metastatic brain tumors.

4. Conclusions

There are several hypothesis for the neurodegeneration process; however, the lack of availability of in vivo models makes the recapitulation of AD in humans impossible. Moreover, the drugs currently available in the market serve to alleviate the symptoms and there is no cure for the disease. There have been two major hurdles in the process of finding the same—the inefficiency in cracking the complexity of the disease pathogenesis and the inefficiency in delivery of drugs targeted for AD. This review discusses the different drugs that have been designed over the recent years and the drug delivery options in the field of nanotechnology that have been found most feasible in surpassing the blood–brain barrier (BBB) and reaching the brain.

Acknowledgments

M.Z.M. was financially supported by the Department of Health and Research, Ministry of Health and Family Welfare, Government of India under young scientist FTS No. 3146887.

Author Contributions

D.-K.K. and M.Z.M. conceived the idea. M.A., M.K.H. and M.R.A. wrote the manuscript. D.-K.K. and M.Z.M. critically revised the manuscript. All authors have read and agree to the published version of the manuscript.

This work was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (No. 2018R1D1A1B07040673, No. 2014R1A5A2010008).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A Research Paper on Alzheimer’s Disease

This research paper will delve into Alzheimer’s Disease, covering its causes, symptoms, progression, and current treatments. It will also explore ongoing research in finding a cure and ways to manage this debilitating condition. On PapersOwl, there’s also a selection of free essay templates associated with Alzheimers Disease.

How it works

In this paper, Alzheimer’s disease will be delved into, investigated and dissected. This will include all that is known about the disease as much of it is unknown still, despite increasing efforts from the medical community to uncover its origin. The disease’s causes, symptoms and stages will be discussed and illuminated. The effects on other body systems, its signs and symptoms and any other complications will be highlighted as well. Additionally, advancements in treating this disease are carefully examined.

In this paper, I will be giving an overview of Alzheimer’s disease. This will include its history, prognosis and treatment available and recent advancements made towards finding a cure. Alzheimer’s disease is a somewhat recently discovered phenomenon. It is a specific type of dementia, a disease that impairs a person’s cognitive functioning and behavioral abilities to the point that it interferes with that person’s daily life. The disease was discovered in 1906 by Dr. Alois Alzheimer who noted shrinkage around nerve cells in his patient’s brain who had also reported,” symptoms of memory loss, paranoia and psychological changes.”, according to the National Institute of Aging. After the patient passed, Dr. Alzheimer dissected her brain, finding strange clumps which we now know are amyloid plaques as well as tangled fibers now called neurofibrillary. Alzheimer’s disease is characterized by the symptoms of the aforementioned patient’s, however the disease is a very slowly progressing one, so most afflicted don’t know until the symptoms become obvious to those around them. “Alzheimer’s disease is the most frequent cause of irreversible dementia in adults. The intellectual impairment progresses gradually from forgetfulness to total impairment.” (Mace, Rabins 15) Symptoms usually appear in a person’s mid-60’s, however there are rare cases of early on-set Alzheimer’s where symptoms are exhibited in a person’s 30’s and 40’s. The disease usually progresses to the point that a person afflicted is unable to take care of themselves due to severe memory loss and loss of motor skills, requiring full time assistance. They may also experience forms of delusion such as hallucinations or paranoia that cause them to act impulsively in the moderate stage of dementia, according to the National Institute of Aging. Most diagnosed with this disease will reach this point sadly, as they usually have an average of eight years left to live after the diagnosis as there is no cure, only treatments. The difficulty in treating Alzheimer’s is highlighted by the fact that the first FDA approved drug to treat it wasn’t available until 1993, almost a full century after its discovery. As of today, there are a total of five FDA approved drugs for treating Alzheimer’s disease, none of which truly treat the disease but only prolong the symptoms that will eventually surface. “If we had a drug or other intervention that made people with Alzheimer’s disease even a little better, nevermind curing the disease, I’d sing its praises to the rooftops.[…] But there is not.” (Dedsen 4)

Alzheimer’s disease affects every body system in humans due to the fact that it destroys the brain. It atrophizes, or shrinks, the brain’s neurons and their networks die off, resulting in shrinking of various brain regions. There is no cure as of yet because there is no known way to reverse deterioration of these precious cells. Warning signs of the disease include symptoms of memory loss, severe enough that it affects job performance, difficulty with familiar tasks, issues with language, difficulty with keeping track of time or place, decreased judgment skills, severe mood changes and inability to recognize loved ones, especially in the late stages of the disease, according to the Alzheimer’s Association. Even a change of a person’s sense of humor can be a warning sign. Most individuals who reach the late stages of this disease will require full time assistance such as live in nurses.

On the bright side, specialists typically accurately diagnose Alzheimer’s at a rate of 95%. The only true way to confirm Alzheimer’s disease is through autopsy, however there are a multitude of tests specialists utilize to differentiate Alzheimer’s from other forms of dementia. These include genetic testing, magnetic resonance imaging, urinalysis, blood tests, electroencephalogram, spinal tap, computed tomography scan, chest X-ray and a mental status test, according to the Alzheimer’s Association. In contrast, the prognosis with treatment for those affected is currently bleak. There are few medications available to those with Alzheimer’s and none prevent or cure the disease. Average life expectancy is eight years after diagnosis, but it can range from one to twenty years for some, all according to the Alzheimer’s Association.

Currently, there are hundreds of studies being conducted on treating and preventing Alzheimer’s disease. Most medications being proposed are modifying therapies, meaning that they could alter how the disease progresses. others include cognitive enhancers for improving memory or attentiveness and lastly symptomatic agents which may lessen symptoms such as hallucinations. The focus areas of research currently being conducted are clinical and laboratory research. Clinical research at the Mayo Clinic Study of Aging focus on normal aging, mild cognitive impairment and dementia disorders. This process is used in the hopes of discovering patterns or signs that may help specialists discover risk of Alzheimer’s even sooner than previously possible. Laboratory research includes studying amyloid and tau proteins. Both of these proteins have strong associations with those at risk for Alzheimer’s and other forms of dementia. Amyloid proteins are being studied with both human and mouse models to determine any genetic factors that might predispose people to this disease. Additionally, tau proteins are being studied to ascertain the possibility of preventing the build up of this protein that causes neurons to malfunction and die, according to the Alzheimer’s Association. Currently, there is no prevention of the disease itself, only medication that may slow down the progress of the disease in certain individuals. There are tests available to help determine if you or a loved one may be at risk, but no prevention. Alzheimer’s is a devastating disease due to the fact that it’s largely out of our control. Later generations may see improvements in treating it or preventing it or ideally finding a cure. However, the fact that it’s been known for over a century and there has yet to be substantial slowing of the progress of the disease through medication, no available prevention and no cure whatsoever is depressing to say the least. It is “the only one of the nation’s leading 10 causes of death for which there is no effective treatment.” (Dedsen 4) However, having said this, there has been a greater push and call for urgency in discovering a cure for the disease. President Obama signed The National Plan to Address Alzheimer’s Disease into effect in January of 2011. This initiative gave greater funding for new research projects, better tools for clinicians, easier access to information to help caregivers and created an awareness campaign, according to the National Institute of Aging. There has even been news about its awareness efforts in pop culture thanks to Seth Rogen and his wife Lauren MIller Rogen, who’s mother passed away due to complications from being diagnosed with Alzheimer’s disease, creating the program, “Hilarity for Charity”. This program is described as being,” a non-profit movement dedicated to raising awareness, inspiring change and accelerating progress in Alzheimer’s care, research and support through the engagement of millenials.” For six years in a row now, the Rogens have put on a stand-up special grouping together various comedians to help raise funds for Alzheimer’s research, the most recent of which can be streamed on netflix. While there is no cure, seeing such a push for progress in understanding and fighting this disease can only give one hope that major advancements will be made in the future.

• About Hilarity for Charity. (n.d.). Retrieved from https://hilarityforcharity.org/about/
• Alzheimer’s Disease Fact Sheet. (2016, August). Retrieved from https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet
• Bredesen, D. (2017) The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline. New York, NY: Penguin Random House.
• R. C. (n.d.). Research and Prognosis on Alzheimer’s Disease. Retrieved from https://www.gulfbend.org/poc/view_doc.php?type=doc&id=3249&cn=231
• Mace, N. L., & Rabins, P. V. (2017). The 36-hour day: A family guide to caring for people who have Alzheimer disease, related dementias and memory loss. New York: Grand Central.
• Obama administration presents national plan to fight Alzheimer’s disease. (n.d.). Retrieved from https://www.nia.nih.gov/news/obama-administration-presents-national-plan-fight-alzheimers-disease
• What Is Alzheimer’s? (n.d.). Retrieved from https://www.alz.org/alzheimers-dementia/what-is-alzheimers

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APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease

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• Alzheimer's disease
• Predictive markers

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

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Data availability.

Access to tabular data from ADNI ( https://adni.loni.usc.edu/ ), OASIS ( https://oasis-brains.org/ ), A4 ( https://ida.loni.usc.edu/collaboration/access/appLicense.jsp ) and NACC ( https://naccdata.org/ ) can be requested online, as publicly available databases. All requests will be reviewed by each studyʼs scientific board. Concrete inquiries to access the WRAP ( https://wrap.wisc.edu/data-requests-2/ ) and ALFA + ( https://www.barcelonabeta.org/en/alfa-study/about-the-alfa-study ) cohort data can be directed to each study team for concept approval and feasibility consultation. Requests will be reviewed to verify whether the request is subject to any intellectual property.

Code availability

All statistical analyses and raw figures were generated using R (v.4.2.2). We used the open-sourced R packages of ggplot2 (v.3.4.3), dplyr (v.1.1.3), ggstream (v.0.1.0), ggpubr (v.0.6), ggstatsplot (v.0.12), Rmisc (v.1.5.1), survival (v.3.5), survminer (v.0.4.9), gtsummary (v.1.7), epitools (v.0.5) and statsExpression (v.1.5.1). Rscripts to replicate our findings can be found at https://gitlab.com/vmontalb/apoe4-asdad (ref. 32 ). For neuroimaging analyses, we used Free Surfer (v.6.0) and ANTs (v.2.4.0).

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Acknowledgements

We acknowledge the contributions of several consortia that provided data for this study. We extend our appreciation to the NACC, the Alzheimer’s Disease Neuroimaging Initiative, The A4 Study, the ALFA Study, the Wisconsin Register for Alzheimer’s Prevention and the OASIS3 Project. Without their dedication to advancing Alzheimer’s disease research and their commitment to data sharing, this study would not have been possible. We also thank all the participants and investigators involved in these consortia for their tireless efforts and invaluable contributions to the field. We also thank the institutions that funded this study, the Fondo de Investigaciones Sanitario, Carlos III Health Institute, the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas and the Generalitat de Catalunya and La Caixa Foundation, as well as the NIH, Horizon 2020 and the Alzheimer’s Association, which was crucial for this research. Funding: National Institute on Aging. This study was supported by the Fondo de Investigaciones Sanitario, Carlos III Health Institute (INT21/00073, PI20/01473 and PI23/01786 to J.F., CP20/00038, PI22/00307 to A.B., PI22/00456 to M.S.-C., PI18/00435 to D.A., PI20/01330 to A.L.) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Program 1, partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una Manera de Hacer Europa. This work was also supported by the National Institutes of Health grants (R01 AG056850; R21 AG056974, R01 AG061566, R01 AG081394 and R61AG066543 to J.F., S10 OD025245, P30 AG062715, U54 HD090256, UL1 TR002373, P01 AG036694 and P50 AG005134 to R.S.; R01 AG027161, R01 AG021155, R01 AG037639, R01 AG054059; P50 AG033514 and P30 AG062715 to S.J.) and ADNI (U01 AG024904), the Department de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca I Innovació en Salut (SLT006/17/00119 to J.F.; SLT002/16/00408 to A.L.) and the A4 Study (R01 AG063689, U24 AG057437 to R.A.S). It was also supported by Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151 o J.F.) and Horizon 2020–Research and Innovation Framework Programme from the European Union (H2020-SC1-BHC-2018-2020 to J.F.; 948677 and 847648 to M.S.-C.). La Caixa Foundation (LCF/PR/GN17/50300004 to M.S.-C.) and EIT Digital (Grant 2021 to J.D.G.) also supported this work. The Alzheimer Association also participated in the funding of this work (AARG-22-923680 to A.B.) and A4/LEARN Study AA15-338729 to R.A.S.). O.D.-I. receives funding from the Alzheimer’s Association (AARF-22-924456) and the Jerome Lejeune Foundation postdoctoral fellowship.

Author information

These authors contributed equally: Juan Fortea, Víctor Montal.

Authors and Affiliations

Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau, Barcelona, Spain

Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Lídia Vaqué-Alcázar, Laura Videla, Alexandre Bejanin, Alberto Lleó & Víctor Montal

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Barcelona, Spain

Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Laura Videla, Alexandre Bejanin, Alberto Lleó & Víctor Montal

Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain

Juan Fortea & Laura Videla

Department of Medicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain

Lídia Vaqué-Alcázar

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain

Juan Domingo Gispert & Marc Suárez-Calvet

Neurosciences Programme, IMIM - Hospital del Mar Medical Research Institute, Barcelona, Spain

Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain

Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina. Instituto de Salud carlos III, Madrid, Spain

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

Sterling C. Johnson

Brigham and Women’s Hospital Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Reisa Sperling

Barcelona Supercomputing Center, Barcelona, Spain

Víctor Montal

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Contributions

J.F. and V.M. conceptualized the research project and drafted the initial manuscript. V.M., J.P. and J.F. conducted data analysis, interpreted statistical findings and created visual representations of the data. O.B. and O.D.-I. provided valuable insights into the genetics of APOE. L.V., A.B. and L.V.-A. meticulously reviewed and edited the manuscript for clarity, accuracy and coherence. J.D.G., M.S.-C., S.J. and R.S. played pivotal roles in data acquisition and securing funding. A.L. and D.A. contributed to the study design, offering guidance and feedback on statistical analyses, and provided critical review of the paper. All authors carefully reviewed the manuscript, offering pertinent feedback that enhanced the study’s quality, and ultimately approved the final version.

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Correspondence to Juan Fortea or Víctor Montal .

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Competing interests.

S.C.J. has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. M.S.-C. has given lectures in symposia sponsored by Almirall, Eli Lilly, Novo Nordisk, Roche Diagnostics and Roche Farma, received consultancy fees (paid to the institution) from Roche Diagnostics and served on advisory boards of Roche Diagnostics and Grifols. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development and Roche Diagnostics. J.D.G. has served as consultant for Roche Diagnostics, receives research funding from Hoffmann–La Roche, Roche Diagnostics and GE Healthcare, has given lectures in symposia sponsored by Biogen, Philips Nederlands, Esteve and Life Molecular Imaging and serves on an advisory board for Prothena Biosciences. R.S. has received personal consulting fees from Abbvie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. O.B. reported receiving personal fees from Adx NeuroSciences outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Almirall, Fujirebio-Europe, Grifols, Eisai, Lilly, Novartis, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche and outside the submitted work. O.B., D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). The remaining authors declare no competing interests.

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Fortea, J., Pegueroles, J., Alcolea, D. et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nat Med 30 , 1284–1291 (2024). https://doi.org/10.1038/s41591-024-02931-w

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• Published: 17 November 2022

Early prediction of Alzheimer's disease using convolutional neural network: a review

• Vijeeta Patil 1 ,
• Manohar Madgi   ORCID: orcid.org/0000-0001-5118-846X 1 &
• Ajmeera Kiran 2  

The Egyptian Journal of Neurology, Psychiatry and Neurosurgery volume  58 , Article number:  130 ( 2022 ) Cite this article

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In this paper, a comprehensive review on Alzheimer's disease (AD) is carried out, and an exploration of the two machine learning (ML) methods that help to identify the disease in its initial stages. Alzheimer's disease is a neurocognitive disorder occurring in people in their early onset. This disease causes the person to suffer from memory loss, unusual behavior, and language problems. Early detection is essential for developing more advanced treatments for AD. Machine learning (ML), a subfield of Artificial Intelligence (AI), uses various probabilistic and optimization techniques to help computers learn from huge and complicated data sets. To diagnose AD in its early stages, researchers generally use machine learning. The survey provides a broad overview of current research in this field and analyses the classification methods used by researchers working with ADNI data sets. It discusses essential research topics such as the data sets used, the evaluation measures employed, and the machine learning methods used. Our presentation suggests a model that helps better understand current work and highlights the challenges and opportunities for innovative and useful research. The study shows which machine learning method holds best for the ADNI data set. Therefore, the focus is given to two methods: the 18-layer convolutional network and the 3D convolutional network. Hence, CNNs with multi-layered fetch more accurate results as compared to 3D CNN. The work also contributes to the use of the ADNI data set, where the classification of training and testing samples is divided with such a number that brings the highest accuracy achieved with 18-layer CNN. The work concentrates on the early prediction of Alzheimer's disease with machine learning methods. Thus, the accuracy achieved is 98% for 18-layer CNN.

Introduction

The deterioration of physical and neurological functions in persons is part of the aging process. Although deterioration is natural, it can significantly influence some persons due to certain risk factors. Alzheimer's disease is a neurocognitive disorder occurring in people in their middle or old age, and it affects 46.8 million people globally and can impact a person's quality of life [ 1 ]. AD populations are estimated to increase to 106.8 million by 2050 [ 2 , 3 ]. The estimated cost of long-term health care for dementia patients is about $290 billion [ 4 ]. Research toward early AD diagnosis is ongoing to slow down the abnormal degradation of neurons in the brain. It also produces emotional and financial benefits for the patient family [ 5 ]. This disease causes the person to suffer from memory loss, unusual behavior, and language problems. It is caused due to the tangled bundles of neurofibrillary fibres of the brain and certain regions of the brain like the entorhinal cortex and hippocampus [ 6 ]. The initial symptoms, such as episodic memory impairment and the navigational problem of the patient, are typical variants. The higher order symptoms include memory loss, impaired judgment, difficulty in identifying objects, confusion in paying bills and driving a vehicle, and placing objects in odd places.

Alzheimer's disease is divided into three periods: the primary period, the intermediate period, and the last period of dementia. AD is diagnosed through the brain monitoring modalities, such as CT (Computer Tomography) scan and PET (Positron Emission Tomography) scan resting-state functional magnetic resonance imaging (RS-FMRI) [ 7 ].

AD is a neurodegenerative disease with symptoms, such as motor dysfunctions of the body. The results of this work created a strong link between inflammation and neurotoxic kynurenines of human samples. A need for biomarkers is necessary due to chronic low-grade inflammation [ 8 ].

The dissection of neuroprotective and neurodegenerative components of AD-affected areas in the brain. It focuses on etiology, pathomechanism, biomarkers, Imaging techniques, and novel therapeutic targets of Alzheimer's disease [ 9 ].

The EEG biomarkers help predict clinical outcomes in patients regularly. The accuracy of psychophysiological biomarkers based on EEG while predicting the outcome of the patients. The machine learning technique reached an accuracy of 83.3%, with EEG-based functional connectivity predicting clinical outcomes in nontraumatic patients [ 10 ].

The neurovisceral integration model of fear is being used. That is, A richer understanding of neurovisceral concomitants of this function has both theoretical and clinical implications [ 11 ].

Treatment of fear-related disorders occurs due to neuro disorder AD. To fix this, research has been done using a novel frequency domain analysis of heart rate using a short-time Fourier transform from a point process modeling algorithm [ 12 ].

Pavlovian and Instrumental learning can be integrated to guide behavior in a phenomenon experimentally known as Pavlovian-to-Instrumental Transfer (PIT) to investigate numerical applications in clinical contexts such as working memory affected due to AD [ 13 ].

Mitochondrial DNA is identified as an inheritable metabolic disease with neurological manifestation and pathogenesis of illness, including neurodegenerative diseases, such as Alzheimer's disease [ 14 ].

Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite with neuroprotective properties. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases, such as Alzheimer's [ 15 ].

• Machine learning

Understanding machine learning and the standard machine learning approaches used in AD prognosis is necessary before starting the deeper examination of machine learning methodologies. Artificial intelligence includes machine learning, which contains various tools for making probabilistic and statistical judgments based on prior knowledge. Classifying new events and forecasting new patterns depends on prior learning (training). When compared to standard statistical methods, machine learning is much more powerful. For machine learning to be successful, it is essential to have a good understanding of the problem and the algorithms' constraints. As a result, it has a fair chance of success if experimentation is carried out appropriately, training is used effectively, and outcomes are rigorously validated.

This paper reviews the state-of-the-art techniques and data sets used to detect Alzheimer's disease. The various researchers' work, different classifiers used to detect Alzheimer's disease early, and the results obtained are discussed. A literature survey is conducted to know every possibility is explored to detect the initial stages of AD using the ML approach. This survey includes a list of methodologies, data sets, and accuracy gained. The study exhibits the most appropriate strategy for quick treatment of AD based on studies conducted from 2016 to 2021.

Mehmood et al. [ 1 ] stated that identifying Alzheimer's on magnetic resonance images in the initial period is carried out using mild cognitive impairment detection using the tissue segmentation of the brain with the help of multiple layers called structured deep learning. The study uses Visual Geometry Group architecture belonging to deep convolutional neural network architecture. The FMRI images used in this paper are gathered from ADNI (Alzheimer's disease neuroimaging initiative) and are found online at adni.loni.usc.edu. To analyze and verify the development of MCI, i.e., mild cognitive impairment, different biomarkers such as structural MRI, PET, and MRI were analyzed and authenticated to detect the traces of AD. 300 MRI subjects were considered and further classified as Alzheimer's, late mild cognitive, and initial mild cognitive periods. The techniques used in this study are CNN with a multi-layered form of various layers, such as convolution layer, pooling layer, and softmax layer. An accuracy of 98.73% is achieved using multi-layered CNN without data augmentation.

Odusami et al. [ 16 ] proposes a deep learning method to detect the early stage of AD. He has proposed a modified ResNet18 model for extracting the features of neuroimaging data from structural magnetic resonance imaging. The data set is fetched from ADNI accessed on January 2021. The data sets are available in DICOMM file format. A total of 413 subjects were considered for the study. The six categories of the database are normal healthy period, light cognitive inability EMCI and notable remembrance, and Alzheimer's is addressed. The techniques used are residual network with 18 layers CNN is proposed. It uses a 3 × 3 seiver, and the phase 1 pooling layer has a 1 × 1 seiver, a completely interlinked, and a softmax layer. The fine-tuned CNN of 18 layered neural networks obtained a separation rate of accuracy of about 99.09%. CNNs are used to detect active magnetic resonance imaging scanned sheets of Alzheimer affected persons. The process is carried out in data collection, preprocessing and fine-tuning, and classification and evaluation stages.

Venugopalan et al. [ 17 ] proposed removing noise from MRI scans using automatic encoders for evoking properties from given data. He has stated a novel method of 3D CNN for imaging data, and he concentrated on the hippocampus brain area and features. Audio oral tests are extracted. The ADNI data set is used considering biological markers MRI, PET, and neuropsychological assessments to measure the progression of mild cognitive impairment. The cross-section Magnetic Resonance scan image gathered about 8209 voxels scattered in 18 parts. A total of 220 patients were considered for the test. The total count of MRI images is 503 in number, SNP is 808 in number, and HER is 2004. A three-tier automatic encoder is used with 199,99, and 51 nodes separately for every part. The first step is to filter noise, and the next is to extract 1680 common features and convert input data into 0's and 1's format by shot encoding. An accuracy of 78% is achieved.

Pradhan et al. [ 18 ] proposed the detection of different stages of AD. The method used is VGG19 and DenseNet169 architecture for classification. The data set is taken from an open online data set library called Kaggle. There are 6000 images labeled as mild, moderate, very mild, and non-demented AD. The features are considered for 80% of learning and 20% of examining phases. VGG19 has around 10–16 convolutional neural network layers. For image classification, DenseNet is used. Here, VGG19 performs better than DenseNet accuracy of 94% is achieved.

Shah et al. [ 19 ] hard and soft voting algorithms were implemented to classify and identify the initial AD period. The data set consists of 437 patients aged between 60 and 96. Among these, 72 people are non-demented, 64 are demented, 70% are used to train the algorithm, and 30% are used to test the algorithm. The classification algorithms are hard voting, soft voting classifiers, and decision tree. SVM is used as a classification method. An accuracy of 84% is obtained for the voting classifier algorithm.

Huanhuan et al. [ 20 ] proposed detecting early stages of dementia (ConvNets) with the help of MRI. The classification of scan images is done using gray color regions and white color regions in the scanned images of the brain. The data are collected from the ADNI database. The number of MRI images collected is 615 in number. The data are segregated in the proportion of 3:1:1. Statistical parameter mapping is used in the preprocessing stage to reduce the patient's head movement, and images are reduced to size 192 × 192 × 160. The techniques used for the detection are based on classifiers eResidual Network of 50 layers, eNeural Architecture Search Network. Adding a dropout layer addresses the overfitting problem to the fully interconnected layer. The accuracy rates are separately obtained from around 97.65% to 88.37% for MCI AD.

Razavi et al. [ 21 ] highlighted using unsupervised feature learning, which has two steps. The first step is to extract features from the raw data. The methods used are scattered filtering and uncontrolled neural layer network. Sparse filtering and regression are called softmax to classify healthy and unhealthy persons. A few unsupervised learning techniques, such as Boltzman machines and dispersed coding, are used to distribute collected data. The data set used in this method is ADNI with cerebrospinal fluids. The total number of AD patients is 51, and 43 patients have mild traces of suffering from AD. The MRI data were obtained using 1.5T scanners. The highest accuracy obtained is 98.3% while using the softmax regression.

Islam et al. [ 22 ] work on AD uses deep learning CNN to analyze brain MRI images. This work also identifies the different stages of the disease. The method also works well with the imbalanced data set. The CNN uses four layers: deep neural layers, batch processing layer, pooling layer, and ReLU layer. According to the 3D brain, MRI data architecture, inception -v4, and Resnet classify the data. The data set used in OASIS has 416 data samples. The training and testing data set is divided into the 4:1 proportion. The performance rates of inception -v4 and Resnet precision rates are 0.81 and 0.82, respectively.

Islam et al. [ 23 ] stated that 3D convolutional neural networks work better in visualizing medical images. Brain PET scans are used to detect Alzheimer's disease using 3D CNN, and five visualization techniques are applied. The data set is collected from ADNI (adni.loni.usc.edu). A total of 1230 PET scans of AD patients are available. The applied visualization techniques are guided by Backpropagation Brain area Occlusion and layerwise relevance propagation. 80% of the data set is used for training, 20% for testing, and the remaining 10% for validation. The visualization techniques are used to enhance and focus on the regions of the brain, such as the frontal mid, precuneus, postcentral, temporal mid, and precentral areas. Hence, the system achieved an efficient classification accuracy of 88.76% is achieved.

Thakare et al. [ 24 ] stated using EEG to detect Alzheimer's disease. The EEG database is extracted from Kashi Bhai Hospital, Pune, and nineteen numbered channels of the EEG database. First, the patients are diagnosed with a clinical diagnosis of MSME. Based on this, the patients are divided into healthy and AD patients. The EEG signals obtained are converted into a.mat file, and the acquisition is made using Simulink. The features extracted from these EEG waves are mean, standard deviation, and mode using wavelet transforms. The classification uses a support vector machine and a normalized minimum distance (NMD) classifier algorithm. An accuracy of 95% is achieved using SVM holds good as compared to the NMD classifier.

Noor et al. [ 25 ] the most popular DL techniques have been explored in detecting those three leading neurological disorders from the MRI scan data. DL methods for the classification of neurological disorders found in the literature have been outlined. The pros, cons, and performance of these DL techniques for the neuroimaging data have been summarized. Prime observation of this study included the maximum usage of CNN in the detection of Alzheimer's disease and Parkinson's disease. On the other hand, DNN has been used with greater prevalence for schizophrenia detection.

Su et al. [ 26 ] Magnetoencephalography (MEG) has been combined with machine learning techniques to recognize Alzheimer's disease (AD), one of the most common forms of dementia. A bimodal recognition system based on an improved score-level fusion approach is proposed to reinforce the interpretation of the brain activity captured by magnetometers and gradiometers. This preliminary study found that the markers derived from the gradiometer tend to outperform the magnetometer-based markers. Interestingly, out of the ten regions of interest, the left-frontal lobe demonstrates about 8% higher mean recognition rate than the second-best performing region (left temporal lobe) for AD/MCI/HC classification.

In clinical practice, several standardized neuropsychological tests have been designed to assess and monitor the neurocognitive status of patients with neurodegenerative diseases, such as Alzheimer's disease. Have presented a robust framework to (i) perform a threefold classification between healthy control subjects, individuals with cognitive impairment, and subjects with dementia using different cognitive indexes and (ii) analyze the variability of the explainability SHAP values associated with the decisions taken by the predictive models [ 27 ].

This study aimed to determine the influence of implementing different ML classifiers in MRI and analyze the use of support vector machines with various multimodal scans for classifying patients with AD/MCI and healthy controls. Conclusions have been drawn in terms of employing different classifier techniques and presenting the optimal multimodal paradigm for AD classification [ 28 ].

Analyzing magnetic resonance imaging (MRI) is a common practice for Alzheimer's disease diagnosis in clinical research. Detection of Alzheimer's disease is exacting due to the similarity in Alzheimer's disease MRI data and standard healthy MRI data of older people. The proposed network can be very beneficial for early stage AD diagnosis. Though the proposed model has been tested only on the AD data set, we believe it can be used successfully for other classification problems in the medical domain [ 29 , 30 ].

A convolutional neural network with multi-layers such as pooling, softmax regression, and completely interconnected layers is used to detect the disease. A CNN increases the size of the images in length and breadth while decreasing the complexity of the image. A pooling process reduces the overfitting problem as the amount of computation and parameters are reduced. The transfer learning model with customized VGG architecture is used to get the highest accuracy rates [ 1 ]: the data collection, preprocessing, fine-tuning, and classification stages. Fine-tuning is used to reduce errors with the help of ImageNet. It uses the residual network with optimal parameters ReLU and stochastic gradient descent. A novel deep learning method with shallow models for integrating data and autoencoders in a minimal data set. VGG 19 of 16 convolutional layers when a large data set is available to classify, and the dense net is utilized to reduce the number of parameters [ 17 ].

DenseNet 169 is used for image classification. Both models are compared; VGG 19 performs better than DenseNet [ 18 ]. Used the support vector machines for classification and used hard and soft voting classifiers to get the optimum accuracy and use of decision trees for regression, making the system fast and efficient in predicting the missing values of the field [ 19 ]. ConvNet for classification and ensemble machine learning techniques are used for a final product from CNN layers. Backpropagation networks either increase or decrease weights to match output with input. Bernoulli's function is used to avoid the overfitting problem [ 20 ]. Sparse filtering and softmax regression are trained automatically to identify healthy and unhealthy individuals. These two methods are called the two-stage learning method [ 21 ]. These are used for deep convolutional neural networks with four functions, pooling, convolution, batch normalization, and rectified linear unit [ 22 ]. The techniques such as 3D convolutional neural networks and visualization techniques include layerwise relevance propagation, guided backpropagation, and sensitivity analysis to detect AD [ 23 ]. Proposed the use of support vector machines and normalized minimum distance classifier, and it uses a supervised learning model for better results [ 24 ]. Table 1 illustrates the list of methodologies.

Comparison of 18-layer CNN and 3D CNN

The two main components of the CNN architecture are a toolkit that analyses and identifies the properties of the image with a process called feature extraction and a second component based on the prediction process, which estimates the image category from the previous stages. A total of five layers are used: CNN layer, max-pooling layer, completely inter-connected layer, activation layer, and dropout layer. This set of five layers is expanded with approximately 240 filters, each of size 5 × 5. The input for these CNN layers is FMRI image, Pet, and CT scan images that undergo all the preprocessing and conversion processes in the proposed methodologies. In the case of 18-layered CNN, the model predicts the output with the highest accuracy as it has to pass through all the bitwise filters. Hence, with 3D CNN networks, the detection of AD disease might be restricted to less accuracy than 26-layered CNN. Detecting damaged neurofibrils in the brain is easily verified with the multi-layered CNN. In the survey of these related works, maximum use of CNN is being done. Figure  1 represents the comparison of multi-layered CNN versus 3D CNN.

Multiple layers convolution neural network architecture versus 3D convolution neural network architecture

The data set used in the following papers is shown in Table 2 , along with the description data set source, the total number of samples used, the count of training and testing samples, and the number of NC—Normal Control, LMCI—Late Mild Cognitive Impairment, EMCI—Early Mild Cognitive Impairment, and Alzheimer's disease.

This section illustrates the results and outcomes of various works shown in Tables 3 , 4 , and 5 and Figs.  2 and 3 .

Comparison of accuracies with different CNNs

Summary of results found in research studies

According to the different works examined, the detection of AD carried out using ResNET18 networks holds the highest accuracy of 98% conducted using seven binary classifications by comparing NC, EMCI, LMCI, and AD. This technique yields efficient accuracy, sensitivity, and specificity results, as considered in previous studies. Tables 4 and 5 list the accuracies from different ML models, such as voting classifiers, decision tree classifiers, SVM, and XG boost algorithms. Table 5 gives the type of CNN network, such as 18-layered CNN with the highest accuracy of 98% and 3D CNN network accuracy 0f 88% to detect Alzheimer's disease.

Early detection of Alzheimer's disease combined with proper cognitive stimulation can reduce the impact on older people and their families. To diagnose this disease, Artificial Intelligence is a study utilized for the early detection of disease in the very first stage. The two most important machine learning algorithms, 18-layered Convolutional Neural Network (CNN) and 3D CNN are used to identify preliminary periods of Alzheimer's disease, implemented on MRI and CT scans and brain monitoring modalities [ 20 ]. The ADNI data set is preferred, and a comparison is made between 18-layered CNN and 3D CNN, focussing on neural networks yielding better results [ 22 , 23 ]. The work illustrates that the best suitable algorithm is 18-layered CNN with an accuracy of 98%, thereby reducing the manual work of the radiologist [ 16 ].

Limitations and future directions

The convolutional neural networks limit the complete detection of AD in the initial stage of the disease. The multi-layered CNN becomes more complex while identifying the affected areas of the brain in old age people. The CNNs do not work with the loss of memory of the patient as there are no signs of it in the sensitive regions of the brain. In the future, the same set of CNNs can also be used parallelly to detect other neurogenerative diseases, such as Parkinson's disease. In future work, the different sets of features can be extracted, and redundant features can be filtered through a convolutional neural network to detect Alzheimer's disease in the seed stage.

This paper compares and evaluates recent research on machine learning techniques for Alzheimer's disease prognosis and prediction. The most recent developments in machine learning have been exposed, including the types of data employed and the effectiveness of machine learning techniques in diagnosing Alzheimer's in its early stages. Machine learning inevitably increases prediction accuracy, especially compared to standard statistical methods. Accuracy resulted in 80–98% using different convolutional neural networks and 3D CNN. The represented methods did not classify the data set as NC, EMCI, and LMCI but considered the local database from Pune hospital of EEG data set for study. In the proposed models, voting classifiers are preferred in monumental state examinations, and clinical counseling is considered. The data set considered in this model is only right-handed people aged between 60 and 96. The data set's classification is not based on the stages of the disease. However, 80% of training and 20% of testing data are distributed and use the DenseNet model and VGG19 architecture, which is why the accuracy reduction by around 87%. The non-classification of a data set based on stages of the disease is the disadvantage of obtaining the lowest accuracy. Using a convolutional neural network with more than 15 layers is best considered for the highest accuracy rate in work as compared to 3D convolutional neural networks.

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Abbreviations

Ambient Assisted Living

Alzheimer's Disease

Artificial Intelligence

Alzheimer's disease neuroimaging ınitiative

Convolutional neural network

Computed Tomography

Digital Imaging and Communications in Medicine

Electroencephalogram

Early mild cognitive ımpairment

Functional magnetic resonance ımaging

Mild cognitive ımpairment

Machine Learning

Magnetic resonance ımage

Mini‐mental state examination

Normal Control

Late Mild Cognitive Impairment

Normalized minimum distance

Open Access Series of Imaging Studies

• Positron Emission Tomography

Resting-state functional magnetic resonance imaging

Single-Nucleotide Polymorphisms

Support vector machine

Visual Geometry Group

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We would like to express our thanks to Dr. Basavaraj Anami, Registrar, KLE Technological University, Hubballi for his valuable suggestions.

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VP: carried the literature review, writer, critical review, and prepared tables. MM: drafted the study, reviewed it critically for important intellectual content and verified the final version of the manuscript. AK: carried the literature review, writer, critical review, and prepared figures. All authors read and approved the final manuscript.

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Patil, V., Madgi, M. & Kiran, A. Early prediction of Alzheimer's disease using convolutional neural network: a review. Egypt J Neurol Psychiatry Neurosurg 58 , 130 (2022). https://doi.org/10.1186/s41983-022-00571-w

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How Did I Get Here? Testing the Translation of the Morris Water Maze and the Influence of Hemoglobin A1c on Spatial Navigation Performance , Colleen Pappas

Improving Dementia Care through Online Training Programs: A Systematic Review and Evaluation , Michelle L. Pleasant

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Moderation Analysis of Bowel Function among Nutrients and Physical Function or Depression, as well as whether Bowel Function is Related to Cognition in Older Adults , Jessie Alwerdt

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Analyzing the effect of complaints, investigation of allegations, and deficiency citations on the quality of care in United States nursing homes (2007 – 2012) , Kevin E. Hansen

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Daily Experiences of Older Adults with Mild Cognitive Impairment , Elizabeth Hahn

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The Relationship between Self-Reported Cancer Pain and Personality in Black and White Older Adults receiving Outpatient Cancer Care , Jessica Krok

Influence of Stress and Cytokinic Profiles on Cognitive Performance in Older Adults , Kerri S. Rawson

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The Role of Lipoproteins/cholesterol in Genomic Instability and Chromosome Mis-segregation in Alzheimer's and Cardiovascular Disease , Antoneta Granic

The Impact of Hospice and Dementia Special Care Units on End-of-Life Care for Individuals with Dementia , Catherine Elizabeth Mccarty

Tarnished Golden Years: Older Offenders with Mental Health Problems and Late Life First Time Offenders , Brianne Stanback

Patient Safety in Nursing Homes , Kali Thomas

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Personality and Adjustment to Assisted Living , Whitney L. Mills

Identifying and Addressing Health Disparities in Black Older Adults with Osteoarthritis , Chivon A. Mingo

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Correlates of attitudes toward behavioral health services among older primary care patients , Nancy Bridger Lynn

Caregivers of adults with intellectual disabilities: The relationship of compound caregiving and reciprocity to quality of life , Elizabeth A. Perkins

Cultural Competence in Health Care: A Client-Based Perspective , Karon L. Phillips

Factors Affecting the Utilization and Quality of Long-Term Care , April Temple

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The Effects of Non-Surgical Interventions on Osteoarthritis-Like Changes in the Mouse Knee , Wendy K. Anemaet

Service Utilization among Bereaved Spouses and Family Caregivers , Elizabeth J. Bergman

The Role of Lifestyle Factors in Cognitive Aging and Dementia , Tiffany F. Hughes

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The preliminary impact of 2001 Florida tort reform on nursing facility litigation in one county , Deborah K. Hedgecock

Measurement equivalence of the center for epidemiological studies depression scale in racially/ethnically diverse older adults , Giyeon Kim

Medicaid risk adjustment model with diagnosis and pharmacy-based adjusters: Does it work? , Yanen Li

Modifiable factors for disability: Is there potential for reducing racial disparities in disability in older age? , Mihaela A. Popa

Community context and health disparities among older adults , Helen M. Zayac

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A three part study on the relationship between retirement planning and health , Linda Christine Albert

Predictors and outcomes of hospice use among Medicare and Medicaid dual-eligible nursing home residents in Florida: a comparison of non-Hispanic Blacks and non-Hispanic Whites , Jung, Kwak

An exploration of middle-aged and older Women's experiences of bat mitzvah within the framework of Erikson's theory of human development , Keren S. Vergon

Theses/Dissertations from 2005 2005

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129 Alzheimer’s Disease Essay Topics & Examples

If you’re writing about patients with memory loss or dementia care and treatment, this article will be of use. Our team has prepared Alzheimer’s disease essay examples and topics below.

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• Therapeutic Dogs, Dementia, Alzheimer’s and Fluid Intelligence It is worth noting that with dementia, the patient has a speech disorder and a personality change in the early stages of the pathology.
• The Alzheimer’s Association Dementia Care Practice Therefore, achieving the philosophy and recommendations of the association is a shared responsibility between doctors, patients, and caregivers. Ultimately, CAPD tests the functionalities of the patient ranging from the psychomotor activities, perceptions, awareness, and orientations, […]
• Dementia, Alzheimer, and Delirium in an Elderly Woman Additionally, she struggles with identifying the appropriate words to use in dialogue and changes the topic. Timing: While in the middle of conversations and public places like supermarkets.
• Alzheimer’s Disease Diagnosis and Intervention The accumulation of plaques and tangles in the brain is a hallmark of the disease, resulting in the death of neurons and a decline in mental capacity.
• Alzheimer’s Disease: Assessment and Intervention The caregiver is recommended to install safety locks and alarms on all doors and windows to prevent the patient from leaving the apartment without supervision.
• Diagnosis of Alzheimer’s or Mild Cognitive Impairment Additionally, it could be mild cognitive impairment as the state shares symptoms with early-onset Alzheimer’s, and if there would be a decline of the signs in the future.
• Management of a Patient With Alzheimer’s: Case Study The correlation between this issue and the probability of the emergence of AD in elderly citizens is proved by the scholars who examined the impact of the quality of air on a person’s health.
• Bilinguals’ Cognitive-Linguistic Abilities and Alzheimer’s Disease This irregularity is reflected in the preserved linguistic abilities, including code-switching and semantic fluency, and the declined functions in translation, picture naming, and phonemic fluency, calling for improved therapy and testing practices.
• Alzheimer’s Disease: Definition, Stages, Diagnosis Alzheimer’s disease is the most common type of dementia, and it is a condition in which the brain stops appropriately performing its functions.
• Fall Risk Assessment of Alzheimer’s Patient The nurse answers questions about the old lady helps fill the Stay Independent brochure and assists the observing physician in carrying the various clinical tests on the patient.
• Alzheimer’s Disease in an Iranian Patient The patient in the company of his son returns to the clinic after four weeks. Since the patient shows no side effects of the disease and an increase in Exelon to 6 mg orally BID […]
• Mr. Akkad and Alzheimer’s Disease: Case Study The onset of the symptoms is reported to have been within the past two years, but the situation has begun to deteriorate, prompting Mr.
• Alzheimer’s Disease: History, Mechanisms and Treatment Nevertheless, researchers state that the development of Alzheimer’s is impacted by the formation of protein plaques and tangles in the brain.
• Alzheimer’s Disease: Causes and Treatment AD is associated with different changes, both cognitive and behavioral. A patient can observe some or all of them depending on the development of the disease.
• Frontotemporal Dementia vs. Alzheimer’s Disease in a Patient Moreover, Alzheimer’s disease affects hypertrophies in the hippocampus as the initial part is involved in the brain’s memory areas and spatial orientation.
• Alzheimer’s Disease: Diagnostic and Treatment Alzheimer’s disease is a progressive degenerative disorder that causes a deterioration of mental and cognitive abilities.
• The Effect of Music on People With Alzheimer’s Disease The evidence suggests that one of the most prominent effects of music on patients with Alzheimer’s disease is autobiographical memory preservation alongside the stimulation of both sympathetic and parasympathetic nervous systems.
• Community Health: Alzheimer’s Disease The community nurse’s role is to develop and participate in primary, secondary, and tertiary preventive strategies and to provide a wide range of nursing care services while maintaining the health and wellbeing of individuals with […]
• Challenges of Living With Alzheimer Disease The medications make the condition of the patient better during the first stages of the disease. During the middle stage of the disease, the symptoms worsen.
• The Burden of Alzheimer’s Disease Assessing the appropriateness and effectiveness of reducing the cost of providing care for patients with Alzheimer remains a major issue that needs to be addressed.
• Chronic Care For Alzheimer’s Disease The application of the Chronic Care Model, in its turn, will serve as the foundation for building the patient’s awareness about their condition, thus, improving the patient’s quality of life and creating the environment, in […]
• Synopsis of Research Studies of Individuals Afflicted by Mild Alzheimer’s Disease The research questions in the articles were tailored along the various physical activities that can assist patients affected by Alzheimer Disease.
• Alzheimer’s Disease and Naturopathic Medicine The main feature of AD is the aggregation of -amyloid. However, application of natural therapies to prohibit the process of the pathways can slow the progress of AD.
• Brain Reduction and Presence of Alzheimer’s Disease The purpose of the study was to examine the correlation between brain reduction and the presence of Alzheimer’s disease. The researchers wanted to examine the nature of such changes in elderly individuals at low risk […]
• Alzheimer Related Morbidity and Death Among New Yorkers Generally, Alzheimer disease is a form of dementia, which inflicts a loss of memory, thinking and behavior. The proportion of ethnic and racial diversity in the US is increasing.
• Environmental Interview on a Patient With Alzheimer Disease In the 1980s, delusions and hallucinations were added as signs of the disease. Researches in the 1960’s show a link between cognitive reduction and the number of ailments in the brain.
• Alzheimer’s Disease Article and Clinical Trial This study shows that environmental hazards, in this case lead, increase the risk of developing Alzheimer’s disease and that the development period is crucial for determining future vulnerability to neurodegeneration and Alzheimer’s disease.
• Alzheimer’s Disease: Regarding Physiology However, one clear aspect of the development of this disease arises from a very complex chain of activities taking place in the brain over a long period of time.
• Mapping the Neurofibrillary Degeneration From Alzheimer’s Disease Patient This is an analytic review of the studies elaborating on the relationship of hyperphosphorylated tau proteins to the development of Alzheimer’s disease and focusing on the antigen capture ELISA specific for p-tau proteins.
• Role of Alzheimer’s Disease Advanced in Our Understanding of the Aging Process Aging on the hand can be defined as the accumulation of different harmful changes in the tissues and cells that raises the possibility of disease and death.
• Depression and Alzheimer’s Disease Moretti et al have studied the relationship between depression and Alzheimer’s disease and explored whether depression is a symptom of AD or comorbidity.
• Alzheimer’s Disease: Medical Analysis Such gene-associated markers have been characterized, in particular the apolipoprotein E gene, which was linked to chromosome# 19, and was responsible for accumulation of A by way of binding to this protein.
• Diabetic Teaching Plan for Alzheimer’s Patient He knows the purposes and some of the steps and needs to be taught again to regain his independence in monitoring his blood glucose level.
• Comparing Alzheimer’s Disease and Parkinson’s Disease There are many superficial similarities between Alzheimer’s disease and Parkinson’s disease primarily in some symptoms and age-group of persons afflicted by these two diseases.
• Alzheimer’s Disease and Long Term Care Alzheimer’s disease is a progressive disease in which memory impairment and disturbances in reasoning and perception are the primary symptoms. Also, well-known skills and recognition of objects and person is diminished in this stage of […]
• The Effects of Alzheimer’s Disease on Family Members The disease develops gradually and is said to be a disease of the old because it relates to the inability to remember.
• Alzheimer’s Disease in Science Daily News Article The news article accurately reports the focus of the study in the diagnosis of AD. Hence, the news article accurately presents that the diagnostic method is important in the diagnosis and prognosis of AD among […]
• Dancing and Risk of Alzheimer’s Disease Despite the fact that there is no effective treatment for Alzheimer’s disease, scientists discovered that dancing could help reduce the severity of the disorder as this activity involves simultaneous brain functioning, which helps to affect […]
• Alzheimer’s Disease Prevalence and Prevention The estimated global prevalence of Alzheimer’s disease is 50 million and is projected to triple by 2050 due to growth in the older generation. According to Alzheimer’s Association, AD is the fifth-ranking killer of persons […]
• Alzheimer’s Disease: Managing Cognitive Dysfunction In the majority of cases, Alzheimer’s disease turns out to be the cause of this problem. Alzheimer’s disease can be caused by different risk factors, but in the majority of cases, it is associated with […]
• Alzheimer’s Disease in Newspaper Articles The number of patients diagnosed with Alzheimer’s and diabetes in the United States, and indeed globally, has increased significantly in the last few years. This means that the main interest of such collaboration is to […]
• Alzheimer’s and Cardiovascular Diseases Progress While the design of the study involves a review of the existing papers and a compilation of their key results, the information provided by the authors is nonetheless crucial to the understanding of the issue.
• Heart Disease and Alzheimer’s in Adult Women Education and Employment History: The patient reported she is a college graduate and has a master’s degree in Victorian Literature. The patient is currently working full-time as a Literature professor at UC Berkeley, in a […]
• The Alzheimer’s Disease Concept In simple words, it is the condition caused by the negative changes in the human brain that, as the end result, leads to memory loss and some behavioral issues that worsen the quality of patient’s […]
• Alzheimer’s Disease, Its Nature and Diagnostics According to the Alzheimer’s Association, this condition is the sixth leading cause of lethal outcomes in the United States. The most frequent symptoms of Alzheimer’s disease include problems with memory, reasoning, thinking processes, perception, and […]
• Alzheimer’s Disease in Medical Research The existing data proposes that if the illness is distinguished before the commencement of evident warning signs, it is probable that the treatments founded on the facts of fundamental pathogenesis will be of assistance in […]
• Alzheimer’s Disease and Antisocial Personality Disorder Since there is currently no cure for Alzheimer’s disease, the future of the nursing care for the people that have the identified disorder concerns mostly maintaining the patient’s quality of life.
• Plasma Amyloid-Beta and Alzheimer’s Disease The impact of AD on public health includes increased rates of informal care and the direct charges of communal care. The aim of this study is to find the precise relationship between plasma amyloid beta […]
• Age Ailment: Dementia and Alzheimer’s Disease It is a time for one to clean the mind and take time to do what matters most in life. With an increased level of technological advancements, a digital sabbatical is mandatory to lower the […]
• Psychology Issues: Alzheimer’s Disease Alzheimer’s disease is a psychological disorder that involves the progressive destruction of brain cells and reduction in the proper functioning of the brain.
• Importance of Drug Therapy in Management of Alzheimer’s Disease The effects of Alzheimer’s disease can be controlled by early detection. Most studies are based on the effects of drug therapy mild Alzheimer’s patients.
• The Development of Alzheimer’s Disease and It’s Effect on the Brain Research studies have revealed that prevalence of the Alzheimer’s disease is increasing exponentially due to change in lifestyles and the incurable nature of the disease.
• Treatment of Alzheimer’s Disease According to documented research, Alzheimer’s disease is the primary cause of dementia affecting close to half a million people in the United Kingdom and five million in the United States.
• Health Care for Elderly People With Alzheimer’s Disease C’s condition is not likely to affect the relationship between her and her relatives if they are sensible toward her. C is to take her to a nursing home for the elderly.
• Diagnosis of Alzheimer’s Disease The most remarkable feature of the disease is the loss of ability to remember events in an individual’s life. According to the latter hypothetical medical study, it has been exemplified that the presence of deposits […]
• Concept and Treatment of the Alzheimer Disorder This implies that cognitive and natural therapies are highly perceived to be effective as opposed to pharmacological treatments. One cannot ignore the fact that both cognitive and natural therapies have become widely accepted in treating […]
• Understanding Alzheimer’s Disease Among Older Population After the 65 years, it has been found that the probability of developing Alzheimer’s disease doubles after every 5 years and as a result, by the age of 85 years, the risk of acquiring the […]
• Concepts of Alzheimer’s Disease The brain changes are the same in both men and women suffering from Alzheimer’s disease. There is also a significant increase in the death of the neurons leading to the shrinking of the affected regions.
• Alzheimer’s Association Of Neurological Disorders And Stroke
• The Potential Treatment of Alzheimer’s Disease: Through CRISPR-Cas9 Genome Editing
• Alzheimer’s Condition as an Enemy of Mental Health
• Vitamin A as a Potential Therapy to Prevent Alzheimer’s Disease
• The Relationship Between Gender And Alzheimer’s Disease
• The Stages and Treatments of Alzheimer’s Disease
• The Clinical Description of the Causes, Symptoms and Treatment of Alzheimer’s Disease
• The Description of Alzheimer’s Disease and Its Statistics in America
• The Psychological Symptoms Of Alzheimer’s The Cognitive Symptoms
• Varying Aspects of Alzheimer’s Disease and Implementations
• The Effects Of Alzheimer’s And Dementia Among Elderly
• The Early Symptoms and Progression of Alzheimer’s Disease
• Watching a Loved One Slip Away from Alzheimer’s Disease
• The Differences Between Dementia And Alzheimer’s Dementia
• A History of Alzheimer’s Disease and Why it is Still One of the Most Researched Diseases Today
• A Healthy Lifestyle Might Help Combat Parkinson’s Disease And Alzheimer’s Disease
• The Studies Of Music And How It May Not Help The Alzheimer’s Disease
• The Trials of Caring For A Loved One With Alzheimer’s Disease
• Alzheimer’s Disease A Progressive And Fatal Disease Of The Brain
• The Effects of Dementia and Alzheimer’s Disease on Caregivers and the Care Needed for Suffering Patients
• The Psychologist’s Role in Addressing Family and Community Problems for Families with Alzheimer’s Disease
• Alzheimer’s Disease and Its Effect on the Patient and Care Giver
• The Statistics of Prevalence of Alzheimer’s Disease in the 21st Century
• The Link Between Down Syndrome and Alzheimer’s Disease
• The Pathophysiology Of Alzheimer’s Disease
• The Causes, Symptoms and Treatment of Alzheimer’s Disease
• The Focus on Alzheimer’s Disease in the Documentary Black Daises for the Bride
• The Physiology and Genetics Behind Alzheimer’s Disease
• The Early Manifestations of Alzheimer’s Disease
• The Role Of Gamma Secretase In Alzheimer’s Disease
• The Lack Of Early Detection Of Alzheimer’s Disease
• The Representation of Alzheimer’s Disease and Its Impact in the Film Still Alice
• The Possible Link of the Human Immune System to Alzheimer’s Disease
• The Study of Alzheimer’s Disease and Its Affect on the Elderly
• The Characteristics, History, Symptoms, Statistics, and Treatment of Alzheimer’s Disease, a Degenerative Brain Disease
• The Triggers, Progression, and Treatment of Alzheimer’s Disease
• Traumatic Brain Injury and Alzheimer’s Disease
• The Positive Impact of Exercise in Protecting the Brain from Alzheimer’s Disease
• Three Primary Types of Dementia: Alzheimer’s Disease, Vascular Dementia
• The Causes, Risks, Factors, and Stages of Alzheimer’s Disease
• The Contingent Valuation Method in Health Care: An Economic Evaluation of Alzheimer’s Disease
• What Is the Difference Between Dementia and Alzheimer’s Disease?
• What Is the Main Cause of Alzheimer’s Disease?
• How Do You Prevent Alzheimer’s Disease?
• Who Is at High Risk for Alzheimer’s Disease?
• What Foods Cause Alzheimer’s Disease?
• Do Alzheimer’s Disease Patients Sleep a Lot?
• Do Alzheimer’s Disease Patients Know They Have It?
• Do Alzheimer’s Disease Patients Feel Pain?
• What Is the Best Treatment for Alzheimer’s Disease?
• How Long Do Alzheimer’s Disease Patients Live?
• What Do Alzheimer’s Disease Patients Think?
• Do People with Alzheimer’s Disease Have Trouble Walking?
• Is End Stage Alzheimer’s Disease Painful?
• What Are the Final Stages of Alzheimer’s Disease Before Death?
• Does Alzheimer’s Disease Run in Families?
• Should You Tell Alzheimer’s Disease Patients the Truth?
• Why Do Alzheimer’s Disease Patients Stop Talking?
• How Do You Know When an Alzheimer’s Disease Patient Is Dying?
• Which Is Worse: Dementia or Alzheimer’s Disease?
• What to Say to Someone Who Has Alzheimer’s Disease?
• How Does Alzheimer’s Disease Affect Eyes?
• Are Alzheimer’s Disease Patients Happy?
• What Are the Warning Signs of Alzheimer’s Disease?
• What Is the Best Way to Help Someone with Alzheimer’s Disease?
• What Are Good Activities for Alzheimer’s Disease Patients?
• Disease Questions
• Disorders Ideas
• Nervous System Research Topics
• Pathogenesis Research Ideas
• Caregiver Topics
• Health Promotion Research Topics
• Neuropsychology Topics
• Therapeutics Research Ideas
• Chicago (A-D)
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IvyPanda. (2024, February 21). 129 Alzheimer’s Disease Essay Topics & Examples. https://ivypanda.com/essays/topic/alzheimers-disease-essay-topics/

"129 Alzheimer’s Disease Essay Topics & Examples." IvyPanda , 21 Feb. 2024, ivypanda.com/essays/topic/alzheimers-disease-essay-topics/.

IvyPanda . (2024) '129 Alzheimer’s Disease Essay Topics & Examples'. 21 February.

IvyPanda . 2024. "129 Alzheimer’s Disease Essay Topics & Examples." February 21, 2024. https://ivypanda.com/essays/topic/alzheimers-disease-essay-topics/.

1. IvyPanda . "129 Alzheimer’s Disease Essay Topics & Examples." February 21, 2024. https://ivypanda.com/essays/topic/alzheimers-disease-essay-topics/.

Bibliography

IvyPanda . "129 Alzheimer’s Disease Essay Topics & Examples." February 21, 2024. https://ivypanda.com/essays/topic/alzheimers-disease-essay-topics/.

Differential Role for Hippocampal Subfields in Alzheimer's Disease Progression Revealed with Deep Learning

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• Affiliation: School of Medicine, Biomedical Research Imaging Center
• Affiliation: College of Arts and Sciences, Department of Computer Science
• Affiliation: School of Medicine, Department of Radiology
• Alzheimer's Disease Neuroimaging Initiative
• Mild cognitive impairment (MCI) is often considered the precursor of Alzheimer's disease. However, MCI is associated with substantially variable progression rates, which are not well understood. Attempts to identify the mechanisms that underlie MCI progression have often focused on the hippocampus but have mostly overlooked its intricate structure and subdivisions. Here, we utilized deep learning to delineate the contribution of hippocampal subfields to MCI progression. We propose a dense convolutional neural network architecture that differentiates stable and progressive MCI based on hippocampal morphometry with an accuracy of 75.85%. A novel implementation of occlusion analysis revealed marked differences in the contribution of hippocampal subfields to the performance of the model, with presubiculum, CA1, subiculum, and molecular layer showing the most central role. Moreover, the analysis reveals that 10.5% of the volume of the hippocampus was redundant in the differentiation between stable and progressive MCI.
• mild cognitive impairment
• hippocampus
• cognitive decline
• Alzheimer's disease
• deep learning
• https://doi.org/10.17615/cq3a-7342
• https://doi.org/10.1093/cercor/bhab223
• In Copyright
• Cerebral Cortex
• National Institute on Aging, NIA: U01AG024904
• Oxford University Press

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Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease

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Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP ) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP . Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.

One Sentence Summary Nasu-Hakola disease causing TYROBP deletion increases the risk of Alzheimer’s disease in elderly monoallelic carriers in the Finnish population.

Competing Interest Statement

CH collaborates with Denali Therapeutics and is a member of the advisory boards of AviadoBio and Cure Ventures. The other authors declare that they have no competing interests.

Funding Statement

This study was funded by the following: Research Council of Finland (to HM, MH, MT, VL). Faculty of Health Sciences, University of Eastern Finland (to HM, MT). Sigrid Juselius Foundation (to MH, VL, ES, TN). The Strategic Neuroscience Funding of the University of Eastern Finland (to MH, AH, VL, ES). Alzheimer's Association (to MH). The State Research Funding KUH-VTR (to VL, ES). Doctoral Programme in Molecular Medicine (to RMW, HJ). Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Nuerology, SyNergy (to CH and SFL) and a Koselleck Project (to CH). JPco-fuND 2019 Personalised Medicine for Neurodegenerative Diseases; PMG-AD (to CH, SFL, JCL, and MH).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Medical Research Ethics committee of Wellbeing Services County of North Savo gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Data Availability

All data associated with this study are present in the paper or the Supplementary Materials. The study participant consent does not allow opening the sequencing (WGS, RNA-seq) or proteomic data generated and analyzed during the current study, but they are available from the corresponding authors (H.M. or M.H.) on reasonable request. Summary statistics from each FinnGen data release will be made publicly available after a one-year embargo period and can be accessed freely at www.finngen.fi/en/access_results. For individual level data, the Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. Access to Finnish Health register data can be applied from Findata (https://findata.fi/en/data/).

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9 Undergraduate Research Projects That Wowed Us This Year

The telegraph. The polio vaccine. The bar code. Light beer. Throughout its history, NYU has been known for innovation, with faculty and alumni in every generation contributing to some of the most notable inventions and scientific breakthroughs of their time. But you don’t wind up in the history books—or peer-reviewed journals—by accident; academic research, like any specialized discipline, takes hard work and lots of practice. 

And at NYU, for students who are interested, that training can start early—including during an undergraduate's first years on campus. Whether through assistantships in faculty labs, summer internships, senior capstones, or independent projects inspired by coursework, undergrad students have many opportunities to take what they’re learning in the classroom and apply it to create original scholarship throughout their time at NYU. Many present their work at research conferences, and some even co-author work with faculty and graduate students that leads to publication. 

As 2023-2024 drew to a close, the NYU News team coordinated with the Office of the Provost to pull together a snapshot of the research efforts that students undertook during this school year. The nine featured here represent just a small fraction of the impressive work we encountered in fields ranging from biology, chemistry, and engineering to the social sciences, humanities, and the arts. 

These projects were presented at NYU research conferences for undergrads, including Migration and Im/Mobility , Pathways for Discovery: Undergraduate Research and Writing Symposium , Social Impact: NYU’s Applied Undergraduate Research Conference , Arts-Based Undergraduate Research Conference , Gallatin Student Research Conference ,  Dreammaker’s Summit , Tandon’s Research Excellence Exhibit , and Global Engagement Symposium . Learn more about these undergrad research opportunities and others.

Jordan Janowski (CAS '24)

Sade Chaffatt (NYU Abu Dhabi '24)

Elsa Nyongesa (GPH, CAS ’24 )

Anthony Offiah (Gallatin ’26)

Kimberly Sinchi (Tandon ’24) and Sarah Moughal (Tandon ’25)

Rohan Bajaj (Stern '24)

Lizette Saucedo (Liberal Studies ’24)

Eva Fuentes (CAS '24)

Andrea Durham (Tandon ’26)

Jordan Janowski (CAS ’24) Major: Biochemistry Thesis title: “Engineering Chirality for Functionality in Crystalline DNA”

Jordan Janowski (CAS '24). Photo by Tracey Friedman

I work in the Structural DNA Nanotechnology Lab, which was founded by the late NYU professor Ned Seeman, who is known as the father of the field. My current projects are manipulating DNA sequences to self-assemble into high order structures.

Essentially, we’re using DNA as a building material, instead of just analyzing it for its biological functions. It constantly amazes me that this is possible.

I came in as a pre-med student, but when I started working in the lab I realized that I was really interested in continuing my research there. I co-wrote a paper with postdoc Dr. Simon Vecchioni who has been a mentor to me and helped me navigate applying to grad school. I’m headed to Scripps Research in the fall. This research experience has led me to explore some of the molecules that make up life and how they could be engineered into truly unnatural curiosities and technologies.

My PI, Prof. Yoel Ohayon , has been super supportive of my place on the  NYU women’s basketball team, which I’m a  member of. He’s been coming to my games since sophomore year, and he’ll text me with the score and “great game!”— it’s been so nice to have that support for my interests beyond the lab.

Anthony Offiah (Gallatin ’26) Concentration: Fashion design and business administration MLK Scholars research project title: “project: DREAMER”

Anthony Offiah (Gallatin '26). Photo by Tracey Friedman

In “project: DREAMER,” I explored how much a person’s sense of fashion is a result of their environment or societal pressures based on their identity. Certain groups are pressured or engineered to present a certain way, and I wanted to see how much of the opposing force—their character, their personality—affected their sense of style. 

This was a summer research project through the MLK Scholars Program . I did ethnographic interviews with a few people, and asked them to co-design their ideal garments with me. They told me who they are, how they identify, and what they like in fashion, and we synthesized that into their dream garments. And then we had a photo shoot where they were empowered to make artistic choices. 

Some people told me they had a hard time conveying their sense of style because they were apprehensive about being the center of attention or of being dissimilar to the people around them. So they chose to conform to protect themselves. And then others spoke about wanting to safeguard the artistic or vulnerable—or one person used the word “feminine”—side of them so they consciously didn’t dress how they ideally would. 

We ended the interviews by stating an objective about how this co-designing process didn’t end with them just getting new clothes—it was about approaching fashion differently than how they started and unlearning how society might put them in a certain box without their approval.  

My concentration in Gallatin is fashion design and business administration. In the industry some clothing is critiqued and some clothing is praised—and navigating that is challenging, because what you like might not be well received. So doing bespoke fashion for just one person is freeing in a sense because you don’t have to worry about all that extra stuff. It’s just the art. And I like being an artist first and thinking about the business second.

Lizette Saucedo (Global Liberal Studies ’24) Major: Politics, rights, and development Thesis title: “Acknowledging and Remembering Deceased Migrants Crossing the U.S.-Mexican Border”

Lizette Saucedo (Global Liberal Studies '24). Photo by Tracey Friedman

My thesis project is on commemorating migrants who are dying on their journey north to cross the U.S.–Mexican border. I look at it through different theoretical lenses, and one of the terms is necropolitics—how politics shapes the way the State governs life and especially death. And then of the main issues aside from the deaths is that a lot of people in the U.S. don’t know about them, due to the government trying to eschew responsibility for migrant suffering. In the final portion of the thesis, I argue for presenting what some researchers call “migrant artifacts”—the personal belongings left behind by people trying to cross over—to the public, so that people can become aware and have more of a human understanding of what’s going on. 

This is my senior thesis for Liberal Studies, but the idea for it started in an International Human Rights course I took with professor Joyce Apsel . We read a book by Jason De León called The Land of the Open Graves , which I kept in the back of my mind. And then when I studied abroad in Germany during my junior year, I noticed all the different memorials and museums, and wondered why we didn’t have the equivalent in the U.S. My family comes from Mexico—my parents migrated—and ultimately all of these interests came together.

I came into NYU through the Liberal Studies program and I loved it. It’s transdisciplinary, which shaped how I view my studies. My major is politics, rights, and development and my minor is social work, but I’ve also studied museum studies, and I’ve always loved the arts. The experience of getting to work one-on-one on this thesis has really fortified my belief that I can combine all those things.

Sade Chaffatt (Abu Dhabi ’24) Major: Biology Thesis title: “The Polycomb repressive component, EED in mouse hepatocytes regulates liver homeostasis and survival following partial hepatectomy.”

Sade Chaffatt (NYU Abu Dhabi '24). Photo courtesy of NYUAD

Imagine your liver as a room. Within the liver there are epigenetic mechanisms that control gene expression. Imagine these epigenetic mechanisms as a dimmer switch, so that you could adjust the light in the room. If we remove a protein that is involved in regulating these mechanisms, there might be dysregulation—as though the light is too bright or too dim. One such protein, EED, plays a crucial role in regulating gene expression. And so my project focuses on investigating whether EED is required in mouse hepatocytes to regulate liver homeostasis and to regulate survival following surgical resection.

Stepping into the field of research is very intimidating when you’re an undergraduate student and know nothing. But my capstone mentor, Dr. Kirsten Sadler , encourages students to present their data at lab meetings and to speak with scientists. Even though this is nerve-wracking, it helps to promote your confidence in communicating science to others in the field.

If you’d asked 16-year-old me, I never would’ve imagined that I’d be doing research at this point. Representation matters a lot, and you often don't see women—especially not Black women—in research. Being at NYUAD has really allowed me to see more women in these spaces. Having had some experience in the medical field through internships, I can now say I’m more interested in research and hope to pursue a PhD in the future.

Kimberly Sinchi (Tandon ’24) Major: Computer Science Sarah Moughal (Tandon ’25) Major: Computer Science Project: Robotic Design Team's TITAN

Sarah Moughal (Tandon '25, left) and Kimberly Sinchi (Tandon '24). Photo by Tracey Friedman

Kimberly: The Robotic Design Team has been active at NYU for at least five years. We’re 60-plus undergrad and grad students majoring in electrical engineering, mechanical engineering, computer science, and integrated design. We’ve named our current project TITAN because of how huge it is. TITAN stands for “Tandon’s innovation in terraforming and autonomous navigation.”

Sarah: We compete in NASA’s lunatics competition every year, which means we build a robot from scratch to be able to compete in lunar excavation and construction. We make pretty much everything in house in the Tandon MakerSpace, and everyone gets a little experience with machining, even if you're not mechanical. A lot of it is about learning how to work with other people—communicating across majors and disciplines and learning how to explain our needs to someone who may not be as well versed in particular technologies as we are. 

Kimberly: With NYU’s Vertically Integrated Project I’ve been able to take what I was interested in and actually have a real world impact with it. NASA takes notes on every Rover that enters this competition. What worked and what didn’t actually influences their designs for rovers they send to the moon and to Mars.

Eva Fuentes (CAS ’24) Major: Anthropology Thesis title: “Examining the relationship between pelvic shape and numbers of lumbar vertebrae in primates”

Eva Fuentes (CAS '24). Photo by Tracey Friedman

I came into NYU thinking I wanted to be an art history major with maybe an archeology minor. To do the archeology minor, you have to take the core classes in anthropology, and so I had to take an intro to human evolution course. I was like, this is the coolest thing I’ve learned—ever. So I emailed people in the department to see if I could get involved. 

Since my sophomore year, I’ve been working in the Evolutionary Morphology Lab with Scott Williams, who is primarily interested in the vertebral column of primates in the fossil record because of how it can inform the evolution of posture and locomotion in humans.

For my senior thesis, I’m looking at the number of lumbar vertebrae—the vertebrae that are in the lower back specifically—and aspects of pelvic shape to see if it is possible to make inferences about the number of lumbar vertebrae a fossil may have had. The bones of the lower back are important because they tell us about posture and locomotion.

I committed to a PhD program at Washington University in St. Louis a few weeks ago to study biological anthropology. I never anticipated being super immersed in the academic world. I don’t come from an academic family. I had no idea what I was doing when I started, but Scott Williams, and everyone in the lab, is extremely welcoming and easy to talk to. It wasn't intimidating to come into this lab at all.

Elsa Nyongesa (GPH, CAS ’24 ) Major: Global Public Health and Biology Project: “Diversity in Breast Oncological Studies: Impacts on Black Women’s Health Outcomes”

Elsa Nyongesa (GPH, CAS '24). Photo by Tracey Friedman

I interned at Weill Cornell Medicine through their Travelers Summer Research Fellowship Program where I worked with my mentor, Dr. Lisa Newman, who is the head of the International Center for the Study of Breast Cancer Subtypes. I analyzed data on the frequency of different types of breast cancer across racial and ethnic groups in New York. At the same time, I was also working with Dr. Rachel Kowolsky to study minority underrepresentation in clinical research. 

In an experiential learning course taught by Professor Joyce Moon Howard in the GPH department, I created a research question based on my internship experience. I thought about how I could combine my experiences from the program which led to my exploration of the correlation between minority underrepresentation in breast oncological studies, and how it affects the health outcomes of Black women with breast cancer.

In my major, we learn about the large scope of health disparities across different groups. This opportunity allowed me to learn more about these disparities in the context of breast cancer research. As a premedical student, this experience broadened my perspective on health. I learned more about the social, economic, and environmental factors influencing health outcomes. It also encouraged me to examine literature more critically to find gaps in knowledge and to think about potential solutions to health problems. Overall, this experience deepened my philosophy of service, emphasizing the importance of health equity and advocacy at the research and clinical level.

Rohan Bajaj (Stern ’24) Major: Finance and statistics Thesis title: “Measuring Socioeconomic Changes and Investor Attitude in Chicago’s Post-Covid Economic Recovery”

Rohan Bajaj (Stern '24). Photo by Tracey Friedman

My thesis is focused on understanding the effects of community-proposed infrastructure on both the socioeconomic demographics of cities and on fiscal health. I’m originally from Chicago, so it made a lot of sense to pay tribute back to the place that raised me. I’m compiling a list of characteristics of infrastructure that has been developed since 2021 as a part of the Chicago Recovery Plan and then assessing how neighborhoods have changed geographically and economically. 

I’m looking at municipal bond yields in Chicago as a way of evaluating the fiscal health of the city. Turns out a lot of community-proposed infrastructure is focused in lower income areas within Chicago rather than higher income areas. So that makes the research question interesting, to see if there’s a correlation between the proposed and developed infrastructure projects, and if these neighborhoods are being gentrified alongside development.

I kind of stumbled into the impact investing industry accidentally from an internship I had during my time at NYU. I started working at a renewable energies brokerage in midtown, where my main job was collecting a lot of market research trends and delivering insights on how these different energy markets would come into play. I then worked with the New York State Insurance Fund, where I helped construct and execute their sustainable investment strategy from the ground up. 

I also took a class called “Design with Climate Change” with Peter Anker in Gallatin during my junior year, and a lot of that class was focused on how to have climate resilient and publicly developed infrastructure, and understanding the effects it has on society. It made me start thinking about the vital role that physical surroundings play in steering communities.

In the short term I want to continue diving into impact-focused investing and help identify urban planners and city government to develop their communities responsibly and effectively.

Andrea Durham (Tandon, ’26)  Major: Biomolecular science Research essay title: “The Rise and Fall of Aduhelm”

Andrea Durham (Tandon '26). Photo by Tracey Friedman

This is an essay I wrote last year in an advanced college essay writing class with Professor Lorraine Doran on the approval of a drug for Alzheimer’s disease called Aduhelm—a monoclonal antibody therapy developed by Biogen in 2021, which was described as being momentous and groundbreaking. But there were irregularities ranging from the design of its clinical trials to government involvement that led to the resignation of three scientists on an advisory panel, because not everybody in the scientific community agreed that it should be approved.

When I was six years old, my grandmother was diagnosed. Seeing the impact that it had over the years broke my heart and ignited a passion in me to pursue research. 

When I started at NYU, I wasn’t really sure what I was going to do in the future, or what opportunities I would go after. This writing class really gave me an opportunity to reflect on the things that were important to me in my life. The September after I wrote this paper, I started volunteering in a lab at Mount Sinai for Alzheimer's disease research, and that’s what I’m doing now—working as a volunteer at the Center for Molecular Integrative Neuroresilience under Dr. Giulio Pasinetti. I have this opportunity to be at the forefront, and because of the work I did in my writing class I feel prepared going into these settings with an understanding of the importance of conducting ethical research and working with integrity.

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Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s

People with two copies of the gene variant APOE4 are almost certain to get Alzheimer’s, say researchers, who proposed a framework under which such patients could be diagnosed years before symptoms.

By Pam Belluck

Scientists are proposing a new way of understanding the genetics of Alzheimer’s that would mean that up to a fifth of patients would be considered to have a genetically caused form of the disease.

Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new designation, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.

It could also mean that hundreds of thousands of people in the United States alone could, if they chose, receive a diagnosis of Alzheimer’s before developing any symptoms of cognitive decline, although there currently are no treatments for people at that stage.

The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world, medical experts said.

“This reconceptualization that we’re proposing affects not a small minority of people,” said Dr. Juan Fortea, an author of the study and the director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say that we don’t know the cause of Alzheimer’s disease,” but, he said, this would mean that about 15 to 20 percent of cases “can be tracked back to a cause, and the cause is in the genes.”

The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have vastly increased risk.

The new study , published in the journal Nature Medicine, analyzed data from over 500 people with two copies of APOE4, a significantly larger pool than in previous studies. The researchers found that almost all of those patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s — not simply a risk factor.

The patients also developed Alzheimer’s pathology relatively young, the study found. By age 55, over 95 percent had biological markers associated with the disease. By 65, almost all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s. And many started developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.

“The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.

She added, “By the time they are picked up and clinically diagnosed, because they’re often younger, they have more pathology.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population, but are an estimated 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population, and about 50 percent of Alzheimer’s dementia patients.

The most common variant is called APOE3, which seems to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer’s experts not involved in the study said classifying the two-copy condition as genetically determined Alzheimer’s could have significant implications, including encouraging drug development beyond the field’s recent major focus on treatments that target and reduce amyloid.

Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, who was not involved in the study, said that patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.

When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black-box warning on the label saying that the medication can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers decided not to offer Leqembi, an intravenous infusion, to such patients.

Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would galvanize interest in developing drugs that are safe and effective for them and add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms.

“Rather than say we have nothing for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages, given how early their pathology starts.

Besides trying to develop drugs, some researchers are exploring gene editing to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s. Another gene-therapy approach being studied involves injecting APOE2 into patients’ brains.

The new study had some limitations, including a lack of diversity that might make the findings less generalizable. Most patients in the study had European ancestry. While two copies of APOE4 also greatly increase Alzheimer’s risk in other ethnicities, the risk levels differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” said Dr. Greicius, who cowrote a study that found that white people with two copies of APOE4 had 13 times the risk of white people with two copies of APOE3, while Black people with two copies of APOE4 had 6.5 times the risk of Black people with two copies of APOE3.

“This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he said, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Under the current genetic understanding of Alzheimer’s, less than 2 percent of cases are considered genetically caused. Some of those patients inherited a mutation in one of three genes and can develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome containing a protein that often leads to what is called Down syndrome-associated Alzheimer’s disease .

Dr. Sperling said the genetic alterations in those cases are believed to fuel buildup of amyloid, while APOE4 is believed to interfere with clearing amyloid buildup.

Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It is unusual for diseases to follow that genetic pattern, called “semidominance,” with two copies of a variant causing the disease, but one copy only increasing risk, experts said.

The new recommendation will prompt questions about whether people should get tested to determine if they have the APOE4 variant.

Dr. Greicius said that until there were treatments for people with two copies of APOE4 or trials of therapies to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status.”

He added, “It will only cause grief at this point.”

Finding ways to help these patients cannot come soon enough, Dr. Sperling said, adding, “These individuals are desperate, they’ve seen it in both of their parents often and really need therapies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

The Fight Against Alzheimer’s Disease

Alzheimer’s is the most common form of dementia, but much remains unknown about this daunting disease..

How is Alzheimer’s diagnosed? What causes Alzheimer’s? We answered some common questions .

A study suggests that genetics can be a cause of Alzheimer’s , not just a risk, raising the prospect of diagnosis years before symptoms appear.

Determining whether someone has Alzheimer’s usually requires an extended diagnostic process . But new criteria could lead to a diagnosis on the basis of a simple blood test .

The F.D.A. has given full approval to the Alzheimer’s drug Leqembi. Here is what to know about i t.

Alzheimer’s can make communicating difficult. We asked experts for tips on how to talk to someone with the disease .

Diet Review: MIND Diet

Finding yourself confused by the seemingly endless promotion of weight-loss strategies and diet plans?  In this series , we take a look at some popular diets—and review the research behind them.

What Is It?

The Mediterranean-DASH Diet Intervention for Neurodegenerative Delay, or MIND diet, targets the health of the aging brain. Dementia is the sixth leading cause of death in the United States, driving many people to search for ways to prevent cognitive decline. In 2015, Dr. Martha Clare Morris and colleagues at Rush University Medical Center and the Harvard Chan School of Public Health published two papers introducing the MIND diet. [1,2] Both the Mediterranean and DASH diets had already been associated with preservation of cognitive function, presumably through their protective effects against cardiovascular disease, which in turn preserved brain health.

The research team followed a group of older adults for up to 10 years from the Rush Memory and Aging Project (MAP), a study of residents free of dementia at the time of enrollment. They were recruited from more than 40 retirement communities and senior public housing units in the Chicago area. More than 1,000 participants filled out annual dietary questionnaires for nine years and had two cognitive assessments. A MIND diet score was developed to identify foods and nutrients, along with daily serving sizes, related to protection against dementia and cognitive decline. The results of the study produced fifteen dietary components that were classified as either “brain healthy” or as unhealthy. Participants with the highest MIND diet scores had a significantly slower rate of cognitive decline compared with those with the lowest scores. [1] The effects of the MIND diet on cognition showed greater effects than either the Mediterranean or the DASH diet alone.

How It Works

The purpose of the research was to see if the MIND diet, partially based on the Mediterranean and DASH diets, could directly prevent the onset or slow the progression of dementia. All three diets highlight plant-based foods and limit the intake of animal and high saturated fat foods. The MIND diet recommends specific “brain healthy” foods to include, and five unhealthy food items to limit. [1]

The healthy items the MIND diet guidelines* suggest include:

• 3+ servings a day of whole grains
• 1+ servings a day of vegetables (other than green leafy)
• 6+ servings a week of green leafy vegetables
• 5+ servings a week of nuts
• 4+ meals a week of beans
• 2+ servings a week of berries
• 2+ meals a week of poultry
• 1+ meals a week of fish
• Mainly olive oil if added fat is used

The unhealthy items, which are higher in saturated and trans fat , include:

• Less than 5 servings a week of pastries and sweets
• Less than 4 servings a week of red meat (including beef, pork, lamb, and products made from these meats)
• Less than one serving a week of  cheese and fried foods
• Less than 1 tablespoon a day of butter/stick margarine

*Note: modest variations in amounts of these foods have been used in subsequent studies. [9,10]

This sample meal plan is roughly 2000 calories, the recommended intake for an average person. If you have higher calorie needs, you may add an additional snack or two; if you have lower calorie needs, you may remove a snack. If you have more specific nutritional needs or would like assistance in creating additional meal plans, consult with a registered dietitian. 

Breakfast: 1 cup cooked steel-cut oats mixed with 2 tablespoons slivered almonds, ¾ cup fresh or frozen blueberries, sprinkle of cinnamon

Snack: 1 medium orange

• Beans and rice – In medium pot, heat 1 tbsp olive oil. Add and sauté ½ chopped onion, 1 tsp cumin, and 1 tsp garlic powder until onion is softened. Mix in 1 cup canned beans, drained and rinsed. Serve bean mixture over 1 cup cooked brown rice.
• 2 cups salad (e.g., mixed greens, cucumbers, bell peppers) with dressing (mix together 2 tbsp olive oil, 1 tbsp lemon juice or vinegar, ½ teaspoon Dijon mustard, ½ teaspoon garlic powder, ¼ tsp black pepper)

Snack: ¼ cup unsalted mixed nuts

• 3 ounces baked salmon brushed with same salad dressing used at lunch
• 1 cup chopped steamed cauliflower
• 1 whole grain roll dipped in 1 tbsp olive oil

Is alcohol part of the MIND diet?

Wine was included as one of the 15 original dietary components in the MIND diet score, in which a moderate amount was found to be associated with cognitive health. [1] However, in subsequent MIND trials it was omitted for “safety” reasons. The effect of alcohol on an individual is complex, so that blanket recommendations about alcohol are not possible. Based on one’s unique personal and family history, alcohol offers each person a different spectrum of benefits and risks. Whether or not to include alcohol is a personal decision that should be discussed with your healthcare provider. For more information, read Alcohol: Balancing Risks and Benefits .

The Research So Far

The MIND diet contains foods rich in certain vitamins, carotenoids, and flavonoids that are believed to protect the brain by reducing oxidative stress and inflammation. Although the aim of the MIND diet is on brain health, it may also benefit heart health, diabetes, and certain cancers because it includes components of the  Mediterranean  and  DASH  diets, which have been shown to lower the risk of these diseases.

Cohort studies

Researchers found a 53% lower rate of Alzheimer’s disease for those with the highest MIND diet scores (indicating a higher intake of foods on the MIND diet). Even those participants who had moderate MIND diet scores showed a 35% lower rate compared with those with the lowest MIND scores. [2] The results didn’t change after adjusting for factors associated with dementia including healthy lifestyle behaviors, cardiovascular-related conditions (e.g., high blood pressure, stroke, diabetes), depression, and obesity, supporting the conclusion that the MIND diet was associated with the preservation of cognitive function.

Several other large cohort studies have shown that participants with higher MIND diet scores, compared with those with the lowest scores, had better cognitive functioning, larger total brain volume, higher memory scores, lower risk of dementia, and slower cognitive decline, even when including participants with Alzheimer’s disease and history of stroke. [3-8]

Clinical trials

A 2023 randomized controlled trial followed 604 adults aged 65 and older who at baseline were overweight (BMI greater than 25), ate a suboptimal diet, and did not have cognitive impairment but had a first-degree relative with dementia. [9] The intervention group was taught to follow a MIND diet, and the control group continued to consume their usual diet. Both groups were guided throughout the study by registered dietitians to follow their assigned diet and reduce their intake by 250 calories a day. The authors found that participants in both the MIND and control groups showed improved cognitive performance. Both groups also lost about 11 pounds, but the MIND diet group showed greater improvements in diet quality score. The authors examined changes in the brain using magnetic resonance imaging, but findings did not differ between groups. [10] Nutrition experts commenting on this study noted that both groups lost a similar amount of weight, as intended, but the control group likely improved their diet quality as well (they had been coached to eat their usual foods but were taught goal setting, calorie tracking, and mindful eating techniques), which could have prevented significant changes from being seen between groups. Furthermore, the duration of the study–3 years–may have been too short to show significant improvement in cognitive function.

The results of this study showed that the MIND diet does not slow cognitive aging over a 3-year treatment period. Whether the MIND diet or other diets can slow cognitive aging over longer time periods remains a topic of intense interest.

Other factors

Research has found that greater poverty and less education are strongly associated with lower MIND diet scores and lower cognitive function. [11]

Potential Pitfalls

• The MIND diet is flexible in that it does not include rigid meal plans. However, this also means that people will need to create their own meal plans and recipes based on the foods recommended on the MIND diet. This may be challenging for those who do not cook. Those who eat out frequently may need to spend time reviewing restaurant menus.
• Although the diet plan specifies daily and weekly amounts of foods to include and not include, it does not restrict the diet to eating only these foods. It also does not provide meal plans or emphasize portion sizes or exercise .

Bottom Line  

The MIND diet can be a healthful eating plan that incorporates dietary patterns from the Mediterranean and DASH , both of which have suggested benefits in preventing and improving cardiovascular disease and diabetes , and supporting healthy aging. When used in conjunction with a balanced plate guide , the diet may also promote healthy weight loss if desired. Whether or not following the MIND diet can slow cognitive aging over longer time periods remains an area of interest, and more research needs to be done to extend the MIND studies in other populations.

• Healthy Weight
• The Best Diet: Quality Counts
• Healthy Dietary Styles
• Other Diet Reviews
• Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL, Bennett DA, Aggarwal NT. MIND diet slows cognitive decline with aging. Alzheimer’s & dementia . 2015 Sep 1;11(9):1015-22.
• Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimer’s & Dementia . 2015 Sep 1;11(9):1007-14.
• Dhana K, James BD, Agarwal P, Aggarwal NT, Cherian LJ, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. MIND diet, common brain pathologies, and cognition in community-dwelling older adults. Journal of Alzheimer’s Disease . 2021 Jan 1;83(2):683-92.
• Cherian L, Wang Y, Fakuda K, Leurgans S, Aggarwal N, Morris M. Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline after stroke. The journal of prevention of Alzheimer’s disease . 2019 Oct;6(4):267-73.
• Hosking DE, Eramudugolla R, Cherbuin N, Anstey KJ. MIND not Mediterranean diet related to 12-year incidence of cognitive impairment in an Australian longitudinal cohort study. Alzheimer’s & Dementia . 2019 Apr 1;15(4):581-9.
• Melo van Lent D, O’Donnell A, Beiser AS, Vasan RS, DeCarli CS, Scarmeas N, Wagner M, Jacques PF, Seshadri S, Himali JJ, Pase MP. Mind diet adherence and cognitive performance in the Framingham heart study. Journal of Alzheimer’s Disease . 2021 Jan 1;82(2):827-39.
• Berendsen AM, Kang JH, Feskens EJ, de Groot CP, Grodstein F, van de Rest O. Association of long-term adherence to the mind diet with cognitive function and cognitive decline in American women. The journal of nutrition, health & aging . 2018 Feb;22(2):222-9. Disclosure: Grodstein reports grants from International Nut Council, other from California Walnut Council, outside the submitted work.
• Chen H, Dhana K, Huang Y, Huang L, Tao Y, Liu X, van Lent DM, Zheng Y, Ascherio A, Willett W, Yuan C. Association of the Mediterranean Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) Diet With the Risk of Dementia. JAMA psychiatry . 2023 May 3.
• Liu X, Morris MC, Dhana K, Ventrelle J, Johnson K, Bishop L, Hollings CS, Boulin A, Laranjo N, Stubbs BJ, Reilly X. Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study: rationale, design and baseline characteristics of a randomized control trial of the MIND diet on cognitive decline. Contemporary clinical trials . 2021 Mar 1;102:106270. Disclosure: several corporations generously donated mixed nuts (International Tree Nut Council Nutrition Research and Education Foundation), peanut butter (The Peanut Institute), extra virgin olive oil (Innoliva-ADM Capital Europe LLP), and blueberries (U.S. Highbush Blueberry Council). These items will be distributed to those participants who are randomized to the MIND diet arm.
• Barnes LL, Dhana K, Liu X, Carey VJ, Ventrelle J, Johnson K, Hollings CS, Bishop L, Laranjo N, Stubbs BJ, Reilly X. Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons. New England Journal of Medicine . 2023 Jul 18.
• Boumenna T, Scott TM, Lee JS, Zhang X, Kriebel D, Tucker KL, Palacios N. MIND diet and cognitive function in Puerto Rican older adults. The Journals of Gerontology: Series A . 2022 Mar;77(3):605-13.

Last reviewed August 2023

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