current alzheimer research journal

Current Alzheimer Research

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Volume 21 , Issues 11, 2024

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Submit to thematic issues, volume 19, issue 6, 2022, mild behavioral impairment: an early sign and predictor of alzheimer's disease dementia.

Pp: 407-419 Author(s): Fei Jiang, Cheng Cheng, Jinsong Huang, Qiaoling Chen and Weidong Le* DOI: 10.2174/1567205019666220805114528 Published on: 23 August, 2022

Ameliorative Effects of Phytomedicines on Alzheimer’s Patients

Pp: 420-439 Author(s): Rekha Khandia*, Neerja Viswanathan, Shailja Singhal, Taha Alqahtani, Mohannad A. Almikhlafi, Alexander Nikolaevich Simonov and Ghulam Md. Ashraf DOI: 10.2174/1567205019666220610155608 Published on: 18 August, 2022

Assessing the Influence of Salvia triloba on Memory Deficit Caused by Sleep Deprivation in the Context of Oxidative Stress

Pp: 440-448 Author(s): Adnan M. Massadeh*, Karem H. Alzoubi, Amal M. Melhim and Abeer M. Rababa’h DOI: 10.2174/1567205019666220805092450 Published on: 23 August, 2022

Vascular Lesions and Brain Atrophy in Alzheimer’s, Vascular and Mixed Dementia: An Optimized 3T MRI Protocol Reveals Distinctive Radiological Profiles

Pp: 449-457 Author(s): Matteo Cotta Ramusino*, Paolo Vitali*, Nicoletta Anzalone, Luca Melazzini, Francesca Paola Lombardo, Lisa Maria Farina, Sara Bernini and Alfredo Costa DOI: 10.2174/1567205019666220620112831 Published on: 04 August, 2022

Effect of Simultaneous Dual-Task Training on Regional Cerebral Blood Flow in Older Adults with Amnestic Mild Cognitive Impairment

Pp: 458-468 Author(s): Yota Kunieda*, Chiaki Arakawa, Takumi Yamada, Shingo Koyama, Mizue Suzuki, Daisuke Ishiyama, Minoru Yamada, Ryuto Hirokawa, Tadamitsu Matsuda, Shintaro Nio, Tomohide Adachi, Haruhiko Hoshino and Toshiyuki Fujiwara DOI: 10.2174/1567205019666220627091246 Published on: 17 August, 2022

Application of Diffusion Tensor Imaging Based on Automatic Fiber Quantification in Alzheimer's Disease

Pp: 469-478 Author(s): Bo Yu, Zhongxiang Ding, Luoyu Wang, Qi Feng, Yifeng Fan, Xiufang Xu* and Zhengluan Liao* DOI: 10.2174/1567205019666220718142130 Published on: 18 August, 2022

Primary Sjögren’s Syndrome Presenting with Rapidly Progressive Dementia: A Case Report

Pp: 479-484 Author(s): Konstantinos Notas, Vasileios Papaliagkas*, Martha Spilioti, Ioannis Papagiannis, Petros Nemtsas, Athanasios Poulopoulos, Konstantinos Kouskouras, Ioannis Diakogiannis and Vasilios K. Kimiskidis DOI: 10.2174/1567205019666220627094707 Published on: 18 July, 2022

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Current and Future Treatments in Alzheimer Disease: An Update

Konstantina g yiannopoulou.

1 Memory Center, Neurological Department, Henry Dunant Hospital Center, Athens, Greece

Sokratis G Papageorgiou

2 Cognitive Disorders/Dementia Unit, 2nd Neurological Department, National and Kapodistrian University of Athens, Attikon General University Hospital, Athens, Greece

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

Introduction

Alzheimer disease (AD) is one of the greatest medical care challenges of our century and is the main cause of dementia. In total, 40 million people are estimated to suffer from dementia throughout the world, and this number is supposed to become twice as much every 20 years, until approximately 2050. 1

Because dementia occurs mostly in people older than 60 years, the growing expansion of lifespan, leading to a rapidly increasing number of patients with dementia, 2 mainly AD, has led to an intensive growth in research focused on the treatment of the disease. However, despite all arduous research efforts, at the moment, there are no effective treatment options for the disease. 3 , 4

The basic pathophysiology and neuropathology of AD that drives the current research suggests that the primary histopathologic lesions of AD are the extracellular amyloid plaques and the intracellular Tau neurofibrillary tangles (NFTs). 5 The amyloid or senile plaques (SPs) are constituted chiefly of highly insoluble and proteolysis-resistant peptide fibrils produced by β-amyloid (Aβ) cleavage. Aβ peptides with Aβ38, Aβ40, and Aβ42 as the most common variants are produced after the sequential cleavage of the large precursor protein amyloid precursor protein (APP) by the 2 enzymes, β-secretase (BACE1) and γ-secretase. Nevertheless, Aβ is not formed if APP is first acted on and cleaved by the enzyme α-secretase instead of β-secretase. 6 According to the “amyloid hypothesis” Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of AD. It is the forming of amyloid oligomers to which neurotoxicity is mainly attributed and initiates the amyloid cascade. The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate), and tau hyperphosphorylation. 5 Tau protein is a microtubule-associated protein which binds microtubules in cells to facilitate the neuronal transport system. Microtubules also stabilize growing axons necessary for neuronal development and function. Abnormally hyperphosphorylated tau forms insoluble fibrils and folds into intraneuronic tangles. Consequently, it uncouples from microtubules, inhibits transport, and results in microtubule disassembly. 6 Although in the amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects. 3 Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (eg, acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD. 5

All of the already established treatments that are used today try to counterbalance the neurotransmitter imbalance of the disease. The acetylocholinesterase inhibitors (AChEIs) which are approved for the treatment of AD are donepezil, galantamine, and rivastigmine. 4 , 5 Their development was based in the cholinergic hypothesis which suggests that the progressive loss of limbic and neocortical cholinergic innervation in AD is critically important for memory, learning, attention, and other higher brain functions decline. Furthermore, neurofibrillary degeneration in the basal forebrain is probably the primary cause for the dysfunction and death of cholinergic neurons in this region, giving rise to a widespread presynaptic cholinergic denervation. The AChEIs increase the availability of acetylcholine at synapses and have been proven clinically useful in delaying the cognitive decline in AD. 7

A further therapeutic agent approved for moderate to severe AD is the low-to-moderate affinity, noncompetitive N -methyl- d -aspartate (NMDA) receptor antagonist memantine. 4 , 5 Memantine binds preferentially to open NMDA receptor–operated calcium channels blocking NMDA-mediated ion flux and ameliorating the dangerous effects of pathologically elevated glutamate levels that lead to neuronal dysfunction. 8

In clinical trials, both Aβ and tau are prime targets for disease-modifying treatments (DMTs) in AD. From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities. 7

A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation or induced by them, including inflammation, oxidative damage, iron deregulation, and cholesterol metabolism blood-brain barrier (BBB) dysfunction or α-synuclein toxicity. 9 - 13

This article will review current nonpharmacological and pharmacological management of the cognitive and behavioral symptoms of AD, with a focus on the medications that are currently FDA (Food and Drug Administration)–approved for the treatment of the cognitive and functional deficits of AD. 10 Pharmacological agents under research in phase 1, 2, and 3 clinical trials in AD will be summarized. 11 - 13

Current management of AD

A multifactorial tailored management of AD is attempted nowadays based in the following components:

• Open physician, caregiver, and patient communication: a sincere and successful conveying of information and feelings between them will offer opportune identifying of symptoms, exact evaluation and diagnosis, and suitable guidance.
• - Consistency and simplification of environment 10 ;
• - Established routines 10 ;
• - Communicative strategies such as calm interactions, providing pleasurable activities, using simple language and “saying no” only when safety is concerned 10 ;
• - Timely planning for legal and medical decisions and needs 10 ;
• - Cognitive behavioral therapy 14 , 15 ;
• - Exercise therapy, light therapy, music therapy. 14 , 15
• - Planned short rest periods for the caregiver;
• - Psychoeducation including preparing for effects of dementia on cognition, function and behaviors, expectations, avoiding situations that can worsen the symptoms or increasing the dangers for safety and well-being
• - Encouraging the development of support networks for the caregivers. 10
• Pharmacological interventions.

FDA-approved AD medications

The AChEIs donepezil, galantamine, rivastigmine, and the NMDA antagonist memantine are the only FDA-approved AD medications. 10

AChEIs attempt at reducing the breakdown of acetylcholine levels in the brain of the patients with AD by inhibiting the responsible enzyme acetylcholinesterase in the synaptic cleft. 5 Thus, AChEIs enhance central cholinergic neurotransmission and finally tend to mitigate decline in cognition at least during the first year of treatment. Further decline occurs, but even temporary discontinuation of these drugs results in rapid decline and is associated with greater risk of nursing home placement. 16

Initiation of AChEI treatment as soon as possible after the diagnosis is preferred as patients who started the AChEI 6 months later showed more rapid cognitive decline than those who started the drug immediately. 17 All 3 AChEIs have proved their treatment benefits in delaying decline, stabilizing, or even improving cognition and activities of daily living in randomized placebo-controlled trials up to 52 weeks duration. 10 , 18 Longer term open-label extension studies support also longer term treatment benefits. 10

Significant efficacy differences among the AChEIs have not been reported. Donepezil and rivastigmine have been approved by FDA for mild, moderate, and severe AD, whereas galantamine for mild and moderate AD. 18

The most common adverse effects are triggered by the cholinomimetic action of the AChEIs on the gastrointestinal tract and often include diarrhea, nausea, and vomiting. Rapid eye movement sleep behavior disorder has been also remarked in some individuals. Administration of the drug after a meal in the morning can minimize all of these adverse effects. The transdermal patch of rivastigmine can induce rash at the site of application. Adverse effects affect usually a 5% to 20% of patients but are mostly transient and mild. The AChEIs may also trigger bradycardia and increase the risk of syncope. Thus, AChEIs are contraindicated in conditions including severe cardiac arrhythmias, especially bradycardia or syncope. They are also contraindicated in active peptic ulcer or gastrointestinal bleeding history and uncontrolled seizures. Slow titration over months to years to a maximal tolerated of the indicated dose is important for the safety of the patients. 17 , 18

Pharmacokinetic characteristics differ among AChEIs: the primary route of elimination for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine is liver and intestine metabolism. Donepezil and galantamine inhibit selectively and reversibly the acetylcholinesterase, whereas rivastigmine is a “pseudo-irreversible” inhibitor of acetylcholinesterase and butyrylcholinesterase. Donepezil has a long elimination half-life of 70 hours and galantamine of 6 to 8 hours. The elimination half-life of rivastigmine is very short (1-2 hours for oral and 3-4 hours for transdermal administration), but the duration of action is longer as acetylcholinesterase and butyrylcholinesterase are blocked for around 8.5 and 3.5 hours, respectively. 10 , 17 , 18

Memantine is a noncompetitive low-affinity NMDA-receptor open-channel blocker and affects glutamatergic transmission. 5 Its main elimination route is unchanged via the kidneys with a half-life of 70 hours. It has been approved by FDA for moderate and severe AD either as monotherapy or in combination with an AChEI. 3 Memantine monotherapy has demonstrated short- and long-term benefits for patients with moderate to severe AD as assessed by different scales evaluating activities of daily living, cognition, and behavioral and psychological symptoms of dementia (BPSD). 19

Memantine can be administered in combination with an AChEI, as they have complementary mechanisms of action. Their combination benefits patients with usually additive effects, without any increase in adverse effects. 14 , 15

Duration and persistence of monotherapy or combination treatment with higher doses in moderate or even in advanced dementia are associated with better global function and outcomes. 20

Medications for BPSD

Antipsychotics and antidepressants remain the main medications for BPSD. Selective serotonin reuptake inhibitors are preferred for treating depression and anxiety. Drugs with low anticholinergic effects and an acceptable tolerability, such as sertraline, citalopram, and escitalopram, are more appropriate. Antipsychotics should be administered only when a significant safety risk for the patient or for the caregivers by aggressive behaviors makes them necessary. Controversial and limited evidence cannot adequately support the use of benzodiazepines, anticonvulsants stimulants, or dextromethorphan/quinidine. Pharmacological approaches to managing BPSD are highly individualized and changeable, depending on patient’s comorbidities, stage of the disease, and symptoms’ severity. 21

Removal of superfluous and deleterious medications

Polypharmacy in older patients with dementia is usual (with a prevalence of 25%-98%). 22 Anticholinergics and sedatives are commonly used inappropriate medications. These drugs are prescribed despite strong evidence (Beers Criteria) that they should be avoided in cognitively vulnerable older persons because of their potential adverse cognitive effects. 23 Estrogen is another commonly prescribed potentially inappropriate medication despite evidence that its use is associated with increased cognitive decline in postmenopausal women. 24

Specific examples of usually prescribed potentially harmful medications in the elderly are diphenhydramine, often taken with acetaminophen for insomnia and pain, benzodiazepines for anxiety, anticholinergics (tolderodine, oxybutynin, tamsulosin) for urinary incontinence, biperiden, and pramipexole for extrapyramidal tremor 25 and sedative/hypnotics for sleep disorders. 26

Treating underlying medical conditions

Careful management of vascular risk factors (hyperlipidemia, diabetes, hypertension) is of paramount importance for patients with AD. Hydration, sleep, and nutrition status should also be closely monitored. Disorders in thyroid function or electrolytes, deficiencies in vitamin B 12 , folate, vitamin D, or systemic conditions and diseases that can affect cognition (infections, eg, urinary tract infection, pain, constipation) should be treated. 27

Current Landscape in Treatment Research for AD

No new drug has been approved by FDA for AD since 2003 and there are no approved DMTs for AD, despite many long and expensive trials. 22 , 28 As a matter of fact, more than 200 research projects in the last decade have failed or have been abandoned. 10 Nevertheless, drug pipeline for AD is still full of agents with mechanisms of action (MOA) that target either disease modification or symptoms. 4 , 10 Some of the recent failures of anti-amyloid agents in phase 3 clinical trials in patients with early-stage, mild, or mild-to-moderate stage AD were semagacestat, 29 bapineuzumab, 30 solanezumab 31 and in similar trials of β-secretase inhibitors (BACE) lanabecestat, 32 verubecestat, 33 and atabecestat. 34

The most popular and broadly accepted explanations for the multiple failures of clinical trials of DMT agents for AD include the too late starting of therapies in disease development, the inappropriate drug doses, the wrong main target of the treatment, and mainly an inadequate understanding of the pathophysiology of AD. 35 A novel approach to the problem seems more technical and mathematical than biological and suggests that the selected trials’ clinical endpoint may be extremely premature, and additionally, the variability in diagnostic markers and end points may result in inaccurate diagnosis of patients’ disease state and is finally a definite source of errors. 28 Given the fact that longer trial durations increase the probability of detecting a significant effect but at the same time increase tremendously the costs, the proposed solution seems to be the use of clinical trial simulators. 28 These simulators are constructed with mathematical, computational, and statistical tools and can predict the likelihood that a strategy and clinical end point selection of a given trial are proper or not, before the initiation of the trial. 36 They can also help in the perfecting of the design of the study; hence, they may augment the probability of success of estimated new drugs or save invaluable time and resources, by indicating earlier the forthcoming failure of any inappropriate therapy. 37 Although the use of clinical trial simulators is not frequent in recent research, 38 should this practice be abandoned, especially when potential treatments for diseases with slow progression and long duration, such as AD, are evaluated. 37

At the same time, current research remains focused on the development of therapeutic approaches to slow or stop the disease progression, taking into consideration every new aspect in the biology of the disease, the diagnostic markers, and the precise diagnosis of disease state of every individual and the design of clinical trials. Furthermore, drug development research for AD has become more complicated as preclinical and prodromal AD populations are potentially included in current trials, as well as traditionally included populations of all the clinical stages of AD dementia. 38 Consequently, current guidance provided by the FDA for AD clinical trials further includes use of fluid or neuroradiological biomarkers in disease staging for preclinical and prodromal AD trials and of a single primary outcome in prodromal AD trials. In addition, the use of clinical trial simulators, Bayesian statistics, and modifiable trial designs is strongly suggested. 4

The National Institute on Aging and the Alzheimer’s Association (NIA-AA) proposed a new framework for research, 39 which requires the application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in AD stages, and can be used to assist clinical trials design.

Tau positron emission tomography (tau PET), neurofilament light, and neurogranin are the new biomarkers that are increasingly used by clinical trials. 40

The above-mentioned biological and statistical advances that are recently integrated in clinical trials may comprise the final assets for succeeding in drug development. The current clinical trials in AD in phases 1, 2, and 3 4 , 11 - 13 are briefly discussed. The tested agents in these trials are classified either as potentially modifying the disease or as symptomatic for the cognitive enhancement, and for the relief of neuropsychiatric symptoms. The new directions in AD clinical trials, such as agents with novel MOA, advanced immunotherapies, the involvement of biomarkers in drug development, and repurposed agents, are highlighted.

A search for phases 1, 2, and 3 “recruiting” or “active but not recruiting” clinical trials for AD in clinicaltrials.gov (accessed August 19, 2019) showed 165 outcomes. The last annual review of the drug development pipeline for AD examined clinicaltrials.gov in February, 2019 (132 agents in 156 trials) and provides information and conclusions available at that time: 28 drugs in 42 clinical trials in phase 3 trials, 74 drugs in 83 phase 2 trials, and 30 drugs in 31 phase 1 trials. 4 The tested agents are classified as DMTs (73%), symptomatic cognitive enhancers (13%), and symptomatic for the treatment of BPSDs (11%). 4 The DMT agents were further separated into small molecules or biologics (monoclonal antibodies [mAbs] and other immunotherapies). The DMT agents were also classified according to their potential MOA as amyloid targeting, as tau-related targeting, and as having other MOA such as anti-inflammatory or metabolic protection, neuroprotection, and growth factor support. 4 The DMTs are suggested to be effective to delay or halt disease progression that would be expressed clinically with long-lasting benefits in cognition over many months to years. Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or BPSD elimination. 10

In this review, agents currently studied as potential DMTs will be discussed. Furthermore, an approach to a future “precision medicine” multifactorial therapeutic model based on biomarkers profile, genetic analysis, neuropsychologic evaluation, and neuroimaging accomplished with risk factors restriction will be attempted. 2 , 3

Currently studied DMTs for AD

Amyloid-related mechanisms—dmts.

The crucial step in AD pathogenesis is the production of amyloid (Aβ), which forms SPs (insoluble and proteolysis-resistant fibrils). The Aβ derives from a protein overexpressed in AD, APP through sequential proteolysis by β-secretase (BACE1) in the extracellular domain and γ-secretase in the transmembrane region. Full-length APP is first cleaved by α-secretase or β-secretase. The APP cleavage by α-secretase leads to nonamyloidogenic pathway, whereas APP cleavage by β-secretase (BACE1) leads to amyloidogenic pathway. Sequential cleavage of APP by BACE1 in the extracellular and γ-secretase in the transmembrane area results in the Aβ production. Major sites of γ-secretase cleavage usually occur in positions 40 and 42 of Aβ, thus Aβ40 and Aβ42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1. On the contrary, the nonamyloidogenic processing is more favored in other cells without BACE1 predominance. 5

“Amyloid hypothesis” suggests that Aβ production in the brain triggers a cascade of pathophysiologic events leading to the clinical expression of AD. Aβ is a protein consisting of 3 main isoforms: Aβ38, Aβ40, and Aβ42. Aβ42 is the most aggregation-prone form and has the tendency to cluster into oligomers. Oligomers can form Aβ-fibrils that will eventually form amyloid plaques. Aβ40 is somewhat aggregation-prone and it is mostly found in the cerebral vasculature as a main component of “cerebral amyloid angiopathy.” Aβ40 usually constitutes more than 50% of total detected Aβ. Aβ38 is soluble, present in the vasculature of patients with sporadic and familial AD. Neurotoxicity is mainly attributed to the forming of amyloid oligomers, which finally initiates the amyloid cascade. 5

Oxidation, inflammation, excessive glutamate, and tau hyperphosphorylation are supposed to be the main pathophysiologic pillars of the cascade. Tau protein binds microtubules in cells to facilitate the neuronal transport system. Microtubules also stabilize growing axons. Hyperphosphorylated tau forms insoluble fibrils and folds into intraneuronic NFTs. Consequently, it inhibits neuronal transport and microtubule function. 2 Although in the initial amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is now equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects. 2 The result of massive neuronal destruction is the shortage and imbalance between neurotransmitters, such as acetylcholine, dopamine, serotonin, and to the cognitive and behavioral symptoms of AD. 5

Consequently, anti-amyloid DMTs have focused on 3 major MOAs: (1) reduction of Aβ42 production (γ-secretase inhibitors, β-secretase inhibitors, α-secretase potentiation), (2) reduction of Aβ-plaque burden (aggregation inhibitors, drugs interfering with metals), and (3) promotion of Aβ clearance (active or passive immunotherapy). 10

Reduction of Aβ42 production

γ-secretase inhibitors.

According to the amyloid hypothesis, amyloidogenic pathway is promoted after the sequential cleavage of APP by BACE1 and γ-secretase. Consequently, the inhibition of these enzymes has been considered as a major therapeutic target. Unluckily, concerning γ-secretase, in addition to APP, this particular enzyme acts on many other substances and cleaves different transmembrane proteins. Notch receptor 1, which is essential for control of normal cell differentiation and communication, is among them. 5 This fact is probably responsible for recent failures in clinical trials with γ-secretase inhibitors: semagacestat 29 was associated with worsening of activities in daily leaving and increased rates of infections and skin cancer, avagacestat 41 was associated with higher rate of cognitive decline and adverse dose-limiting effects (skin cancer) and tarenflurbil which showed low brain penetration. 42 Serious safety concerns for γ-secretase inhibitors remove γ-secretase from the role of appropriate target for the treatment of AD 43 until in depth studies on this key enzyme could help to therapeutically target γ-secretase in a safe way. 44 No γ-secretase modulators are currently studied in phase 1-3 clinical trials. 4

BACE inhibitors

Two BACE inhibitors are still elaborated: elenbecestat (E2609) in phase 2 and umibecestat (CNP520) in phase 3. 4 The later agent is studied in asymptomatic individuals at risk of developing AD (APOE4 homozygotes or APOE4 heterozygotes with elevated amyloid, detected by cerebrospinal fluid [CSF] biomarkers or amyloid PET). 45

Fluid and neuroimaging biomarkers indicative of AD pathology or neurodegeneration are integrated in this study.

However, the clinical trials with the BACE inhibitors lanabecestat, 32 verubecestat, 33 and atabecestat 34 have been recently discontinued due to unexpected difficulties. The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms). 10 , 32 - 34 All agents showed significant and dose-dependent result of reducing CSF Aβ42, but without cognitive or functional benefit while many of them were poorly tolerated and some of them failed in subjects with prodromal AD. These results might support the suggestion that blocking the process of forming of Aβ may be not capable of halting the disease progression. 46

α-secretase modulators

According to the amyloid hypothesis, nonamyloidogenic pathway is promoted after the cleavage of APP by α-secretase. Consequently, the modulation of the enzyme has been considered as a major therapeutic target. However, little is known of the main signaling pathways that could stimulate cleavage of APP by α-secretase. Restricted, nowadays, knowledge assumes that α-secretase activation is promoted through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and may be through γ-aminobutyric acid (GABA) receptor signaling; thus, agents that activate the PI3K/Akt pathway or act as selective GABA receptor modulators are suggested as potential therapeutic drugs for AD. 47 , 48

Etazolate (EHT0202) stimulates the nonamyloidogenic α-secretase pathway acting as a selective modulator of GABA receptors. A previous, phase 2 trial has showed that the agent was safe and well tolerated in patients with mild to moderate AD. However, further evaluation of etazolate in phase 3 trials has not progressed. 48 Etazolate is currently evaluated in animal studies for its preventive effect in post-traumatic stress disorder. 49

Two α-secretase modulators that activate the PI3K/Akt pathway are studied in phase 2 clinical studies: APH-1105 and ID1201. APH-1105 is delivered intranasally and is assessed in mild to moderate AD. 4 ID1201 is a fruit extract of melia toosendan and also induces α-secretase activation. It is evaluated in mild AD. 47

Reduction of Aβ-plaque burden

Aggregation inhibitors (anti-amyloid aggregation agents).

Aggregation inhibitors interact directly with the Aβ peptide to inhibit Aβ42 fiber formation, thus they are considered potential therapeutic for AD.

The last Aβ42 aggregation inhibitor which was tested in humans was the oral agent scyllo-inositol (ELND005). A phase 2 clinical trial in patients with AD did not provide evidence to support a clinical benefit of ELND005 while severe toxicity issues (infections) forced the cessation of the study. Further development of the agent at a lower dose has not progressed in the last 8 years. 50

Nowadays, specific agents in the form of peptidomimetics that inhibit and partially reverse the aggregation of Aβ 42 are tested in transmission electron microscopic studies. KLVFF is a peptide sequence that resembles the hydrophobic central part of the Aβ and gradually replaces natural polypeptides. The KLVFF compound that mainly prevents the aggregation of Aβ 42 and can also dissolve the oligomerics to a limited extend is the final compound 18, which is resilient in proteolytic decomposition. 51

Another newly developed class of peptidomimetics are the “γ-AApeptides.” 52 One of them, compound γ-AA26, seems almost 100-fold as efficient as the compound 18 of the KLVFF in the inhibition of the aggregation of Aβ 42 . 52

In vivo animal studies will be developed to manifest the biological potential of peptidomimetics.

Reduction of Aβ-plaque burden via drugs interfering with metals

Abnormal accumulation or dyshomeostasis of metal ions such as iron, copper, and zinc has been associated with the pathophysiology of AD. 5

Deferiprone is an iron chelating agent which is studied in phase 2 trials in participants with mild and prodromal AD. 4 , 53

A metal protein–attenuating compound, PBT2, has recently progressed in phase 2 AD treatment trials, as it demonstrated promising efficacy data in preclinical studies. 54 In a 3-month phase 2 study, PBT2 succeeded in a 13% reduction of CSF Aβ and an executive function improvement in a dose-related pattern in patients with early AD. 55

Promotion of Aβ clearance (active or passive immunotherapy)

The 2 main immunotherapeutic approaches that intend to promote Aβ clearance and are currently tested in clinical and preclinical studies are active and passive immunization: 56

• Active immunization.

Aβ, phosphorylated tau (ptau) peptides, or specific artificial peptides such as polymerized British amyloidosis (ABri)-related peptide (pBri) 57 are used as immunogens. ABri is a rare hereditary amyloidosis associated with a mutation that results in the production of a highly amyloidogenic protein with a unique carboxyl terminus that has no homology to any other human protein. The pBri peptide corresponds to this terminus and induces an immune response that recognizes Aβ and ptau.

Antigen-presenting cells present the immunogens to B cells. Use of Ab or ptau peptides will produce antibodies to Ab or ptau epitopes, respectively. Use of pBri will produce antibodies to both Aβ and ptau epitopes. 56

• Passive immunization.

Monoclonal Abs to Ab, ptau, or b sheet epitopes are systemically and adequately for BBB penetration infused. As antibodies cross the BBB, they act to clear, degrade, or alternatively disaggregate or neutralize their targets. 56

• Stimulation of innate immunity either by active or passive immunization also ameliorates the pathology of the disease by promoting microglia and macrophage function. 56

Overall, Aβ-targeted strategies seem promising if used very early in the progression of the disease, before the presence of any symptoms; thus, they are developed in current trials in preclinical AD. Strategies that target tau pathology, although promising, bear the risk of toxicity at the moment. Nevertheless, it is hypothesized that, in sporadic late onset AD, ptau and Aβ pathologies could be evolved by separate pathways that can affect each other synergistically. 58 Consequently, it is possible that effective AD immunotherapies must be able to simultaneously target both ptau and Aβ pathologies. 56

Immunotherapeutic approaches have dominated in the past 15 years with negative results until now. However, lessons from these fails have altered the current immunotherapy development research for AD. 56

Active Aβ immunotherapy

Six active immunotherapy agents are currently studied in phase 1, 2, and 3 clinical trials:

CAD106 is an active Aβ immunotherapeutic agent, is studied in preclinical AD under the umbrella of the Alzheimer prevention initiative generation program, which comprises 2 phase 3 studies that evaluate simultaneously the safety and efficacy of CAD106 and umibecestat in asymptomatic individuals at risk of developing AD (60-75 years of age, APOE4 homozygotes, or APOE4 heterozygotes with elevated amyloid in CSF or in amyloid PET). 45

Subjects will be registered in generation study 1 (cohort 1: CAD106 or placebo, cohort 2: umibecestat or placebo) or generation study 2 (umibecestat 50 and 15 mg, or placebo). 45

ABvac40 is evaluated in a phase 2 study, as the first active vaccine against the C-terminal end of Aβ 40 . A phase 1 study was conducted with patients with mild to moderate AD aged 50 to 85 years. Neither incident vasogenic edema nor microhemorrhages were identified. Specific anti-Aβ 40 antibodies were developed in the 92% of the individuals receiving injections of ABvac40. 59

GV1001 peptide (tertomotide) was previously studied as a vaccine against various cancers, whereas now it is evaluated in a phase 2 study for AD. 60

ACC-001 (vanutide cridificar), an Aβ vaccine, was studied in phase 2a extension studies in subjects with mild to moderate AD. It was administered with QS-21 adjuvant. Long-term therapy with this combination was very well tolerated and produced the highest anti-Aβ IgG titers compared with other regimens. 61

UB-311, a synthetic peptide used as Aβ vaccine, has been advanced into an ongoing phase 2 study in patients with mild and moderate AD. In phase 1, it induced a 100% responder rate in patients with AD. The usual adverse effects were swelling in the injection site and agitation. A slower cognitive decline rate was observed in patients with mild AD. 62

Lu AF20513 epitope vaccine is estimated in a phase 1 study in mild AD. 63

The occurrence of encephalitis in previous studies (AN-1792) 64 led to the development of improved anti-Aβ active immunotherapy agents, more specific to Aβ sites less probable to activate T cells, currently studied in clinical trials. 5 , 6

Passive Aβ immunotherapy—via mAbs

Passive Ab immunotherapy via mAbs is the most active and promising class. Cerebral microhemorrhages and vasogenic edema are the main drawbacks in this group of agents. 5 Valuable learning gained from previous failed phase 3 trials of the first agents of this class, bapineuzumab 65 and solanezumab, 66 enlightened the mAbs’ research. Strict inclusion criteria were applied, such as biomarker proof of “amyloid positivity” and enrollment of individuals with preclinical stages of the disease. Furthermore, the design of the studies became more specific and targeted: the characteristics of amyloid-related imaging abnormalities were associated with the dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required. 10

Many ongoing mAbs trials are in phase 3, including aducanumab, 67 gantenerumab, 68 and BAN2401 69 in prodromal and very mild AD, and crenezumab, 70 gantenerumab, and solanezumab 71 in studies for preclinical or at-risk populations. First results from aducanumab and BAN2401 trials suggested, at first, a treatment-related result of reducing in cerebral amyloid burden in agreement to deceleration of cognitive decline in patients with prodromal and very mild AD. 71 , 72 On the contrary, the initial trial of gantenerumab in prodromal AD was prematurely stopped for lack of efficacy, but exploratory analyses suggest that higher dosing of gantenerumab may be needed for clinical efficacy and an open-label extension for participating patients with mild AD is continued, simultaneously with a double-blind, placebo-controlled study in patients with mild AD. 4 , 68 Similarly, until now, solanezumab did not delay rates of brain atrophy. 73

Intravenous doses of LY3002813 (donanemab) and LY3372993 are studied in participants with mild cognitive impairment (MCI) and mild to moderate AD in separate phase 1 clinical studies. 4

Passive Aβ immunotherapy—via immunoglobulins

Anti-Aβ antibodies are included in naturally occurring autoantibodies. In contrast to mAbs, blood-derived human anti-Aβ immunoglobulin G (IgG) Abs are polyclonal, with lower avidity for single Aβ molecules, and higher for a broader range of epitopes, especially in Aβ oligomers and fibrils. The natural presence of antibodies against Aβ has been reported in intravenous immunoglobulin (IVIg); thus, IVIg has been considered as a possible AD treatment. Intravenous immunoglobulin is obtained from plasma of healthy donors and is made up of human Abs mainly of the IgG-type. 5 , 74

Nevertheless, the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD. 74

Another strategy directed at diminishing the accumulation of Aβ in the brain is based in altering the transportation of Aβ through the BBB. A recent therapeutic method performs plasma exchange (PE) with albumin replacement, inducing the shifting of the existing dynamic equilibrium between plasma and brain Aβ. This therapeutic method is based in the following considerations: (1) high levels of Aβ aggregation in the brain are accompanied by low levels of Aβ in CSF in AD, (2) albumin is the main protein transporter in humans, (3) albumin binds around the 90% of the circulating Aβ, and (4) albumin has proved Aβ-binding ability. Consequently, it is suggested that PE-mediated possession of albumin-bound Aβ would increase the shift of free Aβ from CSF to plasma to correct the imbalance between brain and blood Aβ levels. 75

A phase 3 trial called Alzheimer’s Management by Albumin Replacement (AMBAR) in mild and moderate AD assesses PE with several replacement volumes of albumin, with or without intravenous immunoglobulin. 76

Furthermore, an ongoing phase 2 study evaluates IVIg Octagram 10% in mild and moderate AD. 4

A novel immunotherapeutic strategy that targets simultaneously Aβ and tau is represented by the NPT088 agent. NPT088 is a mixture of the capsid protein of bacteriophage M13 (g3p) and human-IgG 1 -Fc. NPT088 reduced Aβ and ptau aggregates and improved cognition in aged Tg2576 mice. The agent is currently assessed in a phase 1 clinical study. 77

Tau-related mechanisms—DMTs

Anti-phospho-tau approaches consist a major potential treatment strategy, even if there are yet no agents with this specific MOA advanced in phase 3 studies.

Only 1 agent with tau-related mechanism is evaluated in phase 2/3, whereas 10 agents that target tau as one of their mechanisms are evaluated in phase 2, and 5 more agents with tau-related mechanism are assessed in phase 1 studies. 4

Prevention of ptau formation

The hyperphosphorylation of tau is induced by kinases. 78 Thus, kinase inhibitors are examined as potential therapeutic approaches targeting tau. Glycogen synthase kinase 3 (GSK3β) has become prominent as a possible therapeutic target. The most studied GSK3 inhibitor is lithium chloride, a therapeutic agent for affective disorders, which seems to prevent phosphorylation of tau in mouse models. Lithium is currently reassessed within the novel framework for drug research. 79

Another GSK-3 inhibitor, tideglusib, did not meet phase 2 clinical endpoints in patients with mild and moderate AD. 80

ANAVEX 2-73 is evaluated in a phase 2 trial, for eligible subjects AD MCI or mild AD. 81 ANAVEX 2-73 is also a GSK-3b inhibitor but additionally it is a high affinity sigma 1 receptor agonist and a low-affinity muscarinic agonist. 4 Results presented at 2019 Alzheimer’s Association International Conference (AAIC) revealed that patients treated with ANAVEX 2-73 had high levels of 2 gut microbiota families, Ruminococcaceae and Porphyromonadaceae, which were associated with improved activities of daily living. The effect might potentially be reversal of the microbiota imbalances and might have a homeostatic effect on the brain-gut-microbiota axis. 81

Inhibitors of tau aggregation

Methylene blue (MB), a known phenothiazine, is evaluated in AD studies as a potential tau aggregation inhibitor. The problem with this drug is that urine is colored blue, resulting in a lack of blinding. A monotherapy trial with MB on mild and moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT00515333","term_id":"NCT00515333"}} NCT00515333 ) has demonstrated some clinical benefit in moderate, but not mild AD. 82 However, the methodology of the study, as blinding is impossible, has been highly criticized. 83

Methylene blue’s derivative TRx0237 (LMTX) which was studied in phase 3 failed finally to show efficacy, and based on the analysis of the results, a new phase 2/3 study named LUCIDITY was started 1 year ago in subjects with mild AD with a lower dose of the agent. 84

Microtubule stabilizers

The microtubule-stabilizing agent davunetide was studied in a phase 2 trial but it did not meet the clinical end points. 85

TPI-287 (abeotaxane), a small molecule derived from taxol, is a microtubule protein modulator. It was administered intravenously to patients with mild to moderate AD in a phase 1/2 study ( {"type":"clinical-trial","attrs":{"text":"NCT01966666","term_id":"NCT01966666"}} NCT01966666 ). First results presented report that the agent was not well tolerated by the participants. 84

IONIS MAPTRx (BIIB080), a microtubule-associated protein tau RNA inhibitor, an antisense oligonucleotide, is assessed in a phase 2 clinical study that is still in the recruiting process of patients with mild AD ( {"type":"clinical-trial","attrs":{"text":"NCT02623699","term_id":"NCT02623699"}} NCT02623699 ). 86

Targeting posttranslational modifications of Tau

Another tau modification that promotes aggregation besides phosphorylation is posttranslational modification by lysine acetylation. Thus, the use of inhibitors of tau acetylation is proposed as a possible therapeutic approach for AD.

Nilotinib is a c-Abl tyrosine kinase inhibitor which is used in patients with leukemia. It also appears to trigger intraneuronal autophagy to clear tau. It is now studied in a phase 2 trial in individuals with mild to moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT02947893","term_id":"NCT02947893"}} NCT02947893 ). 4 , 83

Promotion of Tau clearance—immunotherapy

Recently emerged evidence in various animal models strongly suggests that targeting ptau epitopes is a practical approach to induce antibody responses that are able to promote tau clearance. 81 Hence, a number of active and passive immunotherapy projects have reached clinical trials for AD treatment. 83

Active immunotherapy

AADvac1 contains a synthetic tau peptide and is currently studied in a phase 2 clinical study in mild to moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT02579252","term_id":"NCT02579252"}} NCT02579252 ). 4 , 10 , 83

Passive immunotherapy

ABBV-8E12 is a humanized anti-tau MAb assessed in a phase 2 clinical study in patients with early AD ( {"type":"clinical-trial","attrs":{"text":"NCT02880956","term_id":"NCT02880956"}} NCT02880956 ). 87

BIIB092 is a humanized IgG4 MAb against tau fragments derived from the stem cells of a patient with familial AD. 84 A phase 2 clinical trial assesses the safety and efficacy of the agent in participants with AD MCI and mild AD. 4

RO7105705 (MTAU9937 A) is an anti-tau MAb which is assessed in a phase 2 study in individuals with prodromal and mild AD ( {"type":"clinical-trial","attrs":{"text":"NCT03289143","term_id":"NCT03289143"}} NCT03289143 ). 83 , 88

Three other anti-tau mAbs (BIIB076, JNJ-63733657, and LY3303560) are currently assessed in phase 1 clinical trials. 4

DMTs with other mechanisms

Neuroprotection.

AGB101 (low-dose extended-release levetiracetam) is an SV2A modulator that is assessed in a phase 3 clinical trial as a repurposed agent (approved for use in another indication, not epilepsy but MCI due to AD). It is supposed to reduce neuronal hyperactivity induced by Aβ ( {"type":"clinical-trial","attrs":{"text":"NCT03486938","term_id":"NCT03486938"}} NCT03486938 ) ( Diagram 1 ). 4

DMTs with other mechanisms. DMTs indicate disease-modifying therapies; hMSCs, human mesenchymal stem cells.

BHV4157 (troriluzole) is a glutamate modulator that reduces synaptic levels of glutamate and is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03605667","term_id":"NCT03605667"}} NCT03605667 ). 4

Icosapent ethyl is the eicosapentaenoic acid (EPA) omega-3 fatty acid in a purified form. It is supposed to protect neurons from disease pathology and is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02719327","term_id":"NCT02719327"}} NCT02719327 ). 4

There are also 2 biologics and 24 small molecules with neuroprotection as one of their mechanisms 4 assessed in phase 2 clinical studies and 8 small molecules in phase 1 clinical trials. 4

Anti-inflammatory effects

Although neuroinflammation has been proposed as a possible mechanism for the pathogenesis of AD more than 30 years ago, only recently research is spurred into neuroiflammation probably due to 2 enlightening discoveries: first, there is evidence that activated glial cells are involved in the formation of the brain lesions in AD and second, epidemiological studies revealed that patients with rheumatoid arthritis, who are treated with anti-inflammatory drugs for decades, are spared from AD. 89 Further exploration of the inflammatory mechanisms in the disease showed that activation of glial cells, microglia, and astrocytes induces the production of inflammatory cytokines, mainly interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). More specifically, TNF-α signaling has been proved to exacerbate both Aβ aggregation and tau phosphorylation in vivo, 90 whereas its levels have been found elevated in brain and plasma of patients with AD. 91

According to the previously mentioned neuroinflammatory mechanisms, it is established by multiple biomarker and epidemiological studies of Aβ levels in the CSF and the brain that nonsteroidal anti-inflammatory drugs, complement activation blockers, and other anti-inflammatory agents could postpone the clinical onset of AD if they are timely and for a long time applied, such as in rheumatoid arthritis. 89

Furthermore, the already existing TNF-α inhibitors (TNFIs), which are FDA-approved biologic drugs (mAbs) for the treatment of rheumatoid arthritis, Crohn disease, psoriatic arthritis, and other peripheral inflammatory diseases, are studied as a potential therapeutic strategy for AD. The TNF-α–specific mAbs are the agents infliximab, adalimumab, golimumab, and certolizumab, whereas etanercept is a recombinant fusion protein, which is also a TNFI. 91 The limited BBB penetration of these agents is the main drawback for their development. Peripheral targeting of TNF-α activity is the one proposed method for the tackling of the problem and reengineering of the TNFIs to enable BBB penetration is the other. 91 To sum up, large-scale randomized controlled trials assessing the safety and the effectiveness of TNFIs on patients with AD are warranted.

The following are the anti-inflammatory agents currently assessed in phase 3 clinical trials:

• ALZT-OP1a plus ALZT-OP1b (cromolyn plus ibuprofen) is a combination of a mast cell stabilizer and an anti-inflammatory agent, respectively, assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02547818","term_id":"NCT02547818"}} NCT02547818 ). 4
• COR388 targets a periodontal pathogen acting as bacterial protease inhibitor that reduces neuroinflammation and consequently hippocampal degeneration and is currently assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03823404","term_id":"NCT03823404"}} NCT03823404 ). 4
• Masitinib acts on mast cells as a selective tyrosine kinase inhibitor and a modulator of neuroinflammation. It is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT01872598","term_id":"NCT01872598"}} NCT01872598 ). 4

The following are the anti-inflammatory agents studied in phase 2:

• Elderberry Juice improves the mitochondrial function acting as powerful antioxidant rich in anthocyanins ( {"type":"clinical-trial","attrs":{"text":"NCT02414607","term_id":"NCT02414607"}} NCT02414607 ) and GRF6019, a human plasma protein fraction administered with infusions, based on the hypothesis that brain neuroinflammation can be counteracted by young blood parabiosis ( {"type":"clinical-trial","attrs":{"text":"NCT03520998","term_id":"NCT03520998"}} NCT03520998 , {"type":"clinical-trial","attrs":{"text":"NCT03765762","term_id":"NCT03765762"}} NCT03765762 ). 4
• Anti-inflammatory agents studied in phase 1 are the mAbs AL002, AL003 ( {"type":"clinical-trial","attrs":{"text":"NCT03635047","term_id":"NCT03635047"}} NCT03635047 , {"type":"clinical-trial","attrs":{"text":"NCT03822208","term_id":"NCT03822208"}} NCT03822208 ). 4

Growth factor promotion

NDX-1017 is an hepatocyte growth factor with the role to regenerate neurons, which is studied in a phase 1 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03298672","term_id":"NCT03298672"}} NCT03298672 ). 4

Metabolic effects

Losartan plus amlodipine plus atorvastatin plus exercise is a combination repurposed agent suggested to succeed significant reduction of the vascular risk capable of preserving cognitive function. It is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02913664","term_id":"NCT02913664"}} NCT02913664 ). 4

Candesartan, an angiotensin receptor blocker; formoterol, a β 2 adrenergic receptor agonist; and intranasal insulin glulisine, which rises brain insulin signaling, are currently studied in phase 2 clinical trials ( {"type":"clinical-trial","attrs":{"text":"NCT02646982","term_id":"NCT02646982"}} NCT02646982 , {"type":"clinical-trial","attrs":{"text":"NCT02500784","term_id":"NCT02500784"}} NCT02500784 , {"type":"clinical-trial","attrs":{"text":"NCT02503501","term_id":"NCT02503501"}} NCT02503501 , respectively), whereas intranasal insulin aspart is assessed in a phase 1 clinical study. 4

Stem cell therapies

AstroStem is a stem-cell-based treatment administered 10 times intravenously, which consists of stem cells derived from autologous adipose tissue. AstroStem is currently assessed in a phase 2 study ( {"type":"clinical-trial","attrs":{"text":"NCT03117738","term_id":"NCT03117738"}} NCT03117738 ), whereas hMSCs (human mesenchymal stem cells) treatment is assessed in a phase 1 study ( {"type":"clinical-trial","attrs":{"text":"NCT02600130","term_id":"NCT02600130"}} NCT02600130 ). 4

Symptomatic agents

Symptomatic treatments are agents that target and improve the clinical symptoms of the disease, either cognitive or BPSD, without modifying the pathological steps leading to AD or acting on the evolution of the disease, as DMTs are supposed to do.

Overall, there are 33 symptomatic agents in current trials: 19 agents aim to improve cognition and 14 target BPSD.

Eleven of them are studied in phase 3: 3 cognitive intensifiers and 8 acting on BPSD.

Twenty symptomatic agents are in phase 2: 14 cognitive intensifiers and 6 acting on BPSD.

There are also 2 cognitive intensifiers being studied in phase 1. 4

Arduous research efforts persist to develop effective DMTs for AD, as well as symptomatic therapeutics. A plethora of continuing phase 1, 2, and 3 human studies are focused on various treatment targets in AD. Given the recent experience of a high proportion of lack of success in AD clinical trials on therapeutic agents, more recent trials appear robustly empowered by the integration of developments in biomarkers of AD, of the targeting of a single primary outcome, especially in prodromal AD studies, of the enrollment of earlier populations and the innovative trial designs. 91 - 93

At the same time, innovative research targets the development of more sophisticated diagnostic tools (neuroimaging, fluid, proteomic, and genomic AD biomarkers), whereas prevention studies for the disease are also ongoing. 10

If all these research efforts come to fruition, an effective “precision medicine” context could be applied in every patient with AD in the near future: risk factor elimination, comorbid disease treatment, and personalized advice for lifestyle modification will be provided. An AD biomarkers and neuropsychological evaluation profile will be outlined. Afterward, the patient may start a combination of DMTs tailored to meet his genetic, neuroimaging, biochemical, and neuropsychological requirements. 3 , 94

Furthermore and beyond any DMT perspective, clinicians should always maintain a patient/caregiver-targeted dealing with AD. Establishing a strong therapeutic alliance with the patient and his or her caregivers with a holistic and realistic approach involving psychoeducation, behavioral, and environmental techniques; advanced planning for future care needs; and appropriate pharmaceutical treatment is not only an efficient but also an ethical care in AD.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions: SGP conceptualized the study, developed the proposal and coordinated the project. KGY completed initial data entry and analysis, and wrote the report. Both authors read and approved the final manuscript.

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• Published: 04 June 2024

Alzheimer disease

Microglial senescence is a potential therapeutic target for Alzheimer disease

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A new study published in Acta Neuropathologica has identified prematurely senescent microglia in the vicinity of amyloid-β (Aβ) plaques in the brains of individuals with Alzheimer disease (AD). These dysfunctional cells are thought to be a consequence of Aβ pathology and could represent a target for senolytic drugs, which induce apoptosis of senescent cells.

“Previous research has suggested that AD can induce cell senescence, but the affected range of cell types and relationships with specific stressors were not understood,” explains lead author Nurun Fancy. “We sought to comprehensively describe the affected cells and identify the specific factors that are responsible for inducing senescence.”

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Fancy, N. N. et al. Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics. Acta Neuropathol. 147 , 78 (2024)

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Perspectives and Dynamic Predictive Factors Related to Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD) or Conversion from MCI to AD

Cognitive decline, especially Alzheimer’s disease (AD), is neurodegenerative disorders characterized by the cerebral accumulation of amyloid beta (Aβ) and tau and other proposed pathophysiologies. Mild cognitive impairment (MCI) and AD impair the quality of life of the elderly and pose huge public health burdens to the society. The development of MCI and AD are a consequence of the interaction of genetic and environmental factors including ApoE4 and other genetic risk factors, lifestyle, education level, metabolic... see more

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Cognitive decline, especially Alzheimer’s disease (AD), is neurodegenerative disorders characterized by the cerebral accumulation of amyloid beta (Aβ) and tau and other proposed pathophysiologies. Mild cognitive impairment (MCI) and AD impair the quality of life of the elderly and pose huge public health burdens to the society. The development of MCI and AD are a consequence of the interaction of genetic and environmental factors including ApoE4 and other genetic risk factors, lifestyle, education level, metabolic and vascular factors, nutrition, physical and mental health status, etc. Further understanding of the etiology of MCI and AD, and the key factors deciding the progression from the prodromal stage of dementia to AD, is of fundamental significance. This special thematic issue aims to compile original work and expert reviews on perspectives and dynamic predictive factors of MCI and AD, in order to promote discussion and provide references for future research aimed to fully understand or cure cognitive decline.

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Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of the current state of Alzheimer's disease drug development, identify the challenges, and propose future directions for drug discovery and development. We hope that this collection of articles will contribute to the development of effective therapies to treat Alzheimer's disease, improving the lives of millions of people affected by this devastating disorder.

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Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer’s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain tissue of AD patients and also is found across AD animal models. Neuroinflammation has also been shown across different phases of AD pathology. Indeed, from... see more

Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer’s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain tissue of AD patients and also is found across AD animal models. Neuroinflammation has also been shown across different phases of AD pathology. Indeed, from preclinical to late clinical stages, inflammatory markers, including activated microglial cells, activated astrocytes, elevated levels of pro-inflammatory cytokines, chemokines, caspases and other inflammatory protein markers, have been identified both in cellular and animal preclinical studies, in addition to AD subjects. The wide use of anti-inflammatory agents, particularly non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX) enzymes and subsequent prostanoid production, has spawned epidemiological investigations into the potential therapeutic effects of anti-inflammatories in AD, with numerous but not all suggesting a reduced risk of AD development. Despite this, the use of currently available anti-inflammatory agents has failed to demonstrate efficacy in randomised, double-blind, placebo-controlled AD clinical trials. This scenario raises the question as to whether or not neuroinflammation is a primary contributor to disease progression or is a secondary bystander. If a critical contributor, what inflammatory target might best mitigate the excessive proinflammatory signal that drives disease pathology without adversely impacting the known physiological beneficial roles of inflammatory signaling? The current CAR special issue is seeking primary reviews articles that help defines the role of systemic and/or neuroinflammation in neurodegenerative disorders, including AD and associated dementias but, additionally, Parkinson’s disease (PD) and acute conditions, such as traumatic brain injury and ischemic stroke that may provide a conduit to AD and PD. Likewise, articles on the changing role of microglia and astrocytes in a healthy aging brain are welcomed, as are articles relating to new drug targets within the inflammatory cascade and new drug candidates with solid translational potential are also welcomed.

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Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our understanding of AD, enabling early diagnosis, predicting disease progression, and developing innovative therapeutic interventions. Authors are invited to submit their original research or review articles... see more

Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our understanding of AD, enabling early diagnosis, predicting disease progression, and developing innovative therapeutic interventions. Authors are invited to submit their original research or review articles following the submission guidelines of Current Alzheimer Research. All submitted papers will undergo a thorough peer-review process to ensure high scientific quality and relevance to the theme of this thematic issue. Join us in this thematic issue to contribute to the exciting intersection of deep learning and Alzheimer's disease research. Together, we can pave the way for innovative solutions that advance our understanding of AD and improve patient care.

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Application of Artificial Intelligence (AI) in medical imaging has significantly transformed the field of medical diagnostics, enabling faster and more accurate analyses. This Special Issue aims to gather groundbreaking research and innovative applications that leverage AI to advance medical imaging analysis in the field of dementia and normal aging. We welcome submissions exploring topics on  AI classification of dementia subtypes  AI prediction of AD conversion and dementia disease progression  AI MRI of normal brain aging  Innovative MRI methods and other analysis methods pertaining to normal aging, dementia, MCI, or Alzheimer disease

New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease

Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address the complex challenges posed by Alzheimer's disease. Aims: . Explore Emerging Preventive Measures: Investigate novel strategies and interventions aimed at preventing or delaying the onset... see more

Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address the complex challenges posed by Alzheimer's disease. Aims: . Explore Emerging Preventive Measures: Investigate novel strategies and interventions aimed at preventing or delaying the onset of Alzheimer's disease. This includes lifestyle modifications, neuroprotective interventions, and advancements in public health initiatives. . . Enhance Early Diagnosis: Focus on the development and improvement of early diagnostic tools, biomarkers, and imaging techniques for the accurate and timely identification of Alzheimer's disease. Emphasis will be placed on advancements in precision medicine and artificial intelligence applications. . . Innovative Treatment Approaches: Showcase groundbreaking research in pharmacological and non-pharmacological treatment modalities, including the development of disease-modifying therapies, personalized treatment plans, and targeted interventions to improve cognitive function and quality of life for individuals with Alzheimer's disease. . . Rehabilitation and Support Strategies: Highlight innovative rehabilitation programs and support systems designed to enhance the quality of life for individuals living with Alzheimer's disease and their caregivers. This includes cognitive rehabilitation, assistive technologies, and community-based initiatives. . Scope: This thematic issue invites contributions from researchers, clinicians, and experts in the fields of neuroscience, geriatrics, pharmacology, psychology, public health, and related disciplines. Submissions may include original research articles, reviews, case studies, and perspectives that address, but are not limited to, the following topics: • Molecular and cellular mechanisms underlying Alzheimer's disease. • Lifestyle factors and their impact on Alzheimer's disease risk. • Early diagnostic biomarkers and imaging techniques. • Precision medicine approaches in Alzheimer's disease management. • Pharmacological interventions and drug development. • Non-pharmacological therapeutic strategies. • Rehabilitation programs and cognitive training. • Support systems for individuals with Alzheimer's disease and their caregivers. • Ethical considerations in Alzheimer's disease research and treatment. By assembling a collection of high-quality articles, this thematic issue aims to contribute to the global effort to advance our understanding of Alzheimer's disease and foster the development of effective preventive, diagnostic, and therapeutic strategies. The dissemination of this knowledge is crucial for improving the lives of individuals affected by Alzheimer's disease and advancing our collective efforts towards a world without this devastating neurodegenerative disorder.

Linear and non-linear Signals from the brain: from basic to clinical application

Neurodegenerative diseases are increasing in the general population and have been defined by the World Health Organization (WHO) and Alzheimer's Disease International (ADI) as a global public health priority. Data from the WHO Global Action Plan 2017-2025 indicates that in 2015, neurodegeneration-related diseases affected 47 million people worldwide, a figure expected to increase to 75 million by 2030 and 132 million by 2050, with approximately 10 million new cases per year (1 every 3 seconds).... see more

Neurodegenerative diseases are increasing in the general population and have been defined by the World Health Organization (WHO) and Alzheimer's Disease International (ADI) as a global public health priority. Data from the WHO Global Action Plan 2017-2025 indicates that in 2015, neurodegeneration-related diseases affected 47 million people worldwide, a figure expected to increase to 75 million by 2030 and 132 million by 2050, with approximately 10 million new cases per year (1 every 3 seconds). The estimated costs are over $1 trillion annually, with a progressive increase and a continuing challenge for health services. Neuro-degeneration is closely linked to age, and in an ageing society, the impact of the phenomenon is alarming. It is expected that these pathologies will quickly become one of the most relevant problems in terms of public health. In addition to pharmacological interventions and cognitive training, neuroimaging techniques and linear analysis methods have provided new insight into those pathologies. However, in recent years, non-linear methods such as fractal dimension have been successfully applied to electrophysiology and hemodynamic signals, providing a measure of predictability and regularity across different areas of neuroscience, such as consciousness research, mood and anxiety disorders, schizophrenia, neurodevelopmental and neurodegenerative disorders, as well as physiological changes across the lifespan. Despite the extensive research on the fractal structure (fractality) and scale-free dynamics in the brain and the considerable progress made, a comprehensive picture has yet to emerge and needs further linking to a mechanistic account of brain function. Measuring brain complexity in terms of the fractal dimension or other linear and non-linear methods can help us better understand brain functions and identify new biomarkers. This special issue aims: To stress linear and non-linear methods to increase understanding of brain dynamics. Once understood, this unifying principle will help solve the puzzle of brain function. Systems that possess scale-freeness in terms of both structure (fractality) and dynamics (scale-free) may be able to exhibit emergent properties that link spatial and temporal scales. This fundamental principle can help guide both our mechanistic understanding of brain function and the construction of more powerful computational models and algorithms that approach the capabilities of the biological brain. To further discuss identifying and classifying brain cortical areas based on neuronal dynamics rather than cytoarchitectural features. We deem this step to improve our knowledge of the brain’s structural–functional unity. Better knowledge of this aspect could enhance the understanding of the functional aspect of the brain and its deterioration in pathological conditions. To offer an overview of the potential of linear and non-linear methods on non-invasive neuroimaging and electrophysiological techniques as a new economical biomarker, shaping novel research applications in neurophysiology.

Virtual reality-based interventions for cognitive rehabilitation in Alzheimer’s disease

Virtual reality (VR) has been a widely used tool for the rehabilitation of patients in the last two decades, both in the motor and cognitive aspects. VR-based applications are a form of non-pharmacological therapy that has proven effective as an adjuvant treatment. VR has also been shown to be a tool that can improve the quality of life and well-being of people with dementia. Although great progress has been made in the motor aspect, there... see more

Virtual reality (VR) has been a widely used tool for the rehabilitation of patients in the last two decades, both in the motor and cognitive aspects. VR-based applications are a form of non-pharmacological therapy that has proven effective as an adjuvant treatment. VR has also been shown to be a tool that can improve the quality of life and well-being of people with dementia. Although great progress has been made in the motor aspect, there is still a long way to go in the field of cognitive rehabilitation. Numerous studies are highlighting that the cognitive test batteries currently being used lack sufficient ecological validity. In this sense, applications developed under VR have a lot of potential to become more ecologically valid tools. For this reason, it is necessary to test new approaches and conduct more experiments that provide clearer evidence to corroborate the results obtained to date. This is the great objective of this special issue. Therefore, we encourage authors, from academia and industry, to submit both original research and review articles in the field of VR applications intended for cognitive training, cognitive assessment and cognitive rehabilitation in patients with Alzheimer's disease.

Leading Alzheimer Disease Prevention with Precision Health Strategies.

The rising numbers of patients with Alzheimer’s disease (AD) is a concerning reality in our society. Despite tremendous public-private efforts, finding an appropriate treatment for Alzheimer’s disease prevention has not been successful. One of the reasons behind this failure is the push for finding “a treatment that fits all sizes” and ignoring the focus on “the right drug, the right dose, and the right people”. Notably, AD patients have several clinical comorbidities, such as diabetes,... see more

The rising numbers of patients with Alzheimer’s disease (AD) is a concerning reality in our society. Despite tremendous public-private efforts, finding an appropriate treatment for Alzheimer’s disease prevention has not been successful. One of the reasons behind this failure is the push for finding “a treatment that fits all sizes” and ignoring the focus on “the right drug, the right dose, and the right people”. Notably, AD patients have several clinical comorbidities, such as diabetes, obesity, cardiovascular issues, hyperlipidemia, circadian disruption, chronic stress, depression, and anxiety, etc., due to a combination of genetic, metabolic, and lifestyle variability. This demonstrates the complex heterogeneous nature of the possible underlying causes of cognitive disability in the AD population and provides a strong reason to focus on targeted intervention strategies for different target sub-categories of the AD population. Precision medicine approach focuses on individual risk factors that may specifically affect the response to treatments and thus provides a unique opportunity to use individual genetic, metabolic, lifestyle, and co-existing medical conditions to provide personalized treatment. Therefore, focusing on a precision medicine approach can lead to better and more effective therapeutic options for a multifactorial complex disease, such as Alzheimer’s disease.

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Digital Health Technologies for Alzheimer’s Disease and Related Dementias: Initial Results from a Landscape Analysis and Community Collaborative Effort

• Open access
• Published: 06 June 2024

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• Sarah Averill Lott 1 ,
• E. Streel 2 ,
• S. L. Bachman 3 ,
• K. Bode 4 ,
• J. Dyer 5 ,
• C. Fitzer-Attas 6 ,
• J. C. Goldsack 1 ,
• A. Hake 7 ,
• A. Jannati 8 , 9 ,
• R. S. Fuertes 10 &
• P. Fromy 1  

Digital health technologies offer valuable advantages to dementia researchers and clinicians as screening tools, diagnostic aids, and monitoring instruments. To support the use and advancement of these resources, a comprehensive overview of the current technological landscape is essential. A multi-stakeholder working group, convened by the Digital Medicine Society (DiMe), conducted a landscape review to identify digital health technologies for Alzheimer’s disease and related dementia populations. We searched studies indexed in PubMed, Embase, and APA PsycInfo to identify manuscripts published between May 2003 to May 2023 reporting analytical validation, clinical validation, or usability/feasibility results for relevant digital health technologies. Additional technologies were identified through community outreach. We collated peer-reviewed manuscripts, poster presentations, or regulatory documents for 106 different technologies for Alzheimer’s disease and related dementia assessment covering diverse populations such as Lewy Body, vascular dementias, frontotemporal dementias, and all severities of Alzheimer’s disease. Wearable sensors represent 32% of included technologies, non-wearables 61%, and technologies with components of both account for the remaining 7%. Neurocognition is the most prevalent concept of interest, followed by physical activity and sleep. Clinical validation is reported in 69% of evidence, analytical validation in 34%, and usability/feasibility in 20% (not mutually exclusive). These findings provide clinicians and researchers a landscape overview describing the range of technologies for assessing Alzheimer’s disease and related dementias. A living library of technologies is presented for the clinical and research communities which will keep findings up-to-date as the field develops.

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Introduction

T he uses for digital health technologies (DHTs) for clinical research, personalized medicine, and general wellness are well established and continue to expand ( 1 , 2 ). In the field of Alzheimer’s disease and related dementias (ADRD), growth in the development and use of DHTs ( 3 ) is occurring alongside increased research and development of drugs for the prevention and treatment of Alzheimer’s disease (AD) and other dementia-inducing disorders including Lewy Body and frontotemporal dementias( 4 – 6 ). The recent regulatory approval of some therapeutic agents targeting AD pathophysiology highlights the complexity of dementia management, as new treatment opportunities emerge alongside ongoing challenges in dementia research, clinical management, and holistic patient care ( 7 ). These challenges include identifying digital biomarkers that signal changes early in the disease course when intervention is more likely to provide a substantial impact; assessing clinical manifestations of dementia such as activities of daily living (ADLs), cognitive function, physical activity, and sleep; evaluating and demonstrating response to therapeutic interventions ( 8 ); and improving recruitment (including recruitment of diverse patient groups ( 9 ), retention, and assessment of participants in clinical trials). In addressing these challenges, clinicians and researchers will benefit from utilizing DHTs as fit for purpose tools that can play a strategic role in screening, monitoring, and longitudinal assessment in research, clinical, and real world settings.

Members of a global, multi-stakeholder working group convened by the Digital Medicine Society (DiMe) ( 10 ) met over several months to assess the characteristics of DHTs in ADRD populations, recognizing the immense opportunity for further research and clinical impact alongside the ever-increasing burden of Alzheimer’s disease and related dementias ( 11 , 12 ). DiMe, a global non-profit dedicated to driving scientific progress and broad acceptance in digital medicine to redefine healthcare and improve lives, hosts the Digital Health Measurement Collaborative Community (DATAcc) ( 13 ), a U.S. Food and Drug Administration (FDA) Center for Diagnostic and Radiological Health (CDRH) collaborative community ( 14 ), and convenes a wide range of stakeholders and subject matter experts in pre-competitive forums to advance the field.

While others have examined the evidence for ADRD-relevant DHTs ( 15 , 16 ), such efforts are often limited to a subset of available technologies or therapeutic domains, obscuring substantial portions of the DHT landscape and restricting opportunities for translation of the benefits of these tools across different dementias. To obtain a more comprehensive view, our ADRD working group aggregated multiple technologies across ADRD-therapeutic areas by surveying 20 years of peer-reviewed literature and then sourcing additional evidence from DHT users and developers. While we were primarily informed by the literature and had strict inclusion and exclusion criteria, our purpose in this exercise was to identify and collect digital health technologies in use for dementia measurement, not to interrogate the literature for quality or bias as one would expect in a traditional systematic literature review. Rather, our broad landscape assessment was literature-based and community supported, as the DiMe working group (comprised of ADRD experts from clinical, pharmaceutical, industry research and development, and patient advocacy domains; see acknowledgments for complete list of participating organizations) were given an opportunity to review the findings and identify additional technologies for consideration.

The results of this innovative effort are reported here, bringing an open science perspective and outlining the state of digital innovation in ADRD research. As a precompetitive group representing a range of interests, we do not promote any specific technology type, product, or developer in this analysis and therefore refrain from providing direct product examples in-text; a list of all sources that inform this overview is provided in the supplement so that interested readers may seek specific examples if desired. Here we provide a general overview advancing awareness of the range of technologies and their uses for dementia assessment.

Data Sources

The working group sought to identify DHTs with associated evidence of validity ( 17 ) and therefore started by turning to the peer-reviewed literature. In May 2023, we conducted a landscape review to identify DHTs being used for assessment in ADRD populations by the clinical and research communities. The search strings (see supplementary material) included terminology to identify DHTs, diagnostic and descriptive terms to focus on ADRD-relevant populations, and pertinent concepts of interest measured by a DHT including sleep health, memory, language, social function, oculomotor function, cognition, life space mobility, essential bodily functioning, and emotional or behavioral concerns. The selection of these concepts of interest was informed by literature focused on meaningful aspects of health( 8 , 18 , 19 ) for ADRD stakeholders at large. We restricted search results to primary research studies with human participants published within the last 20 years. To avoid over-representation of any given technology brand, we intentionally did not include any name-brand affiliated keywords in the search terms, knowing this might mean relevant studies were omitted from the results if they included only brand identifiers for utilized technologies. The search string was performed within PubMed, APA PsycInfo, and Embase literature databases, and the results were then aggregated and deduplicated within reference management software Zotero ( 20 ).

Literature Review Screening

Identified articles were screened by two reviewers (SAL, PF), with a random sample of 5% co-reviewed to ensure harmony on inclusion/exclusion standards. Articles were included or excluded based on the criteria outlined in Table 1 .

From each qualifying manuscript, we extracted the name and manufacturer of the technology being utilized; the technology type, form factor, and wear location; the reported therapeutic category and population descriptors as described verbatim by study authors; and the general health concepts and outcomes under assessment. Categories used elsewhere in assessing and categorizing DHTs informed our classification labels ( 21 , 22 ) for technology types and health outcomes. Technology types were sorted into ambient (standalone, not worn on the body), wearable (worn on the body for any period of time), implantable (surgically placed), or ingestible (swallowed); while form factor descriptions were as provided by study authors in the text. Broad health outcome categories were sorted into activities of daily living, mental health, neurocognitive, neurological or sensory, physical activity, and sleep. More specific health outcome category labels were derived from study descriptors and are also reported. Lastly, we labeled evidence according to the type of data it reported: verification, analytical validation, clinical validation, and usability or feasibility ( 17 ). When extracting these evidence types and other characteristics such as diagnostic classifications, study populations descriptors, or outcome measures, we adhered to author/publication verbiage as closely as possible with the goal of collating rather than interpreting labels or assessing individual pieces of evidence as to their rigor or performance.

Community Sourcing

ADRD subject matter experts in DHT development, clinical trials, and clinical care from the DiMe ADRD project team ( 10 ) reviewed and added to the list of technologies created during extraction, to identify additional technologies not captured in our literature search. Developers of identified DHTs were contacted by email (when contact information was accessible) and provided a survey via a Qualtrics ( 23 ) link where they could return peer reviewed articles, conference posters or presentations, regulatory documents, datasets, open-source algorithms, or other supporting materials for their technologies in line with the V3 framework ( 17 ). If a developer responded and provided any evidence, that data was assessed against the same inclusion and exclusion standards for the literature presented in Table 1 and included in our results if eligible. Finally, the survey link and a description of the library were shared on LinkedIn during World Alzheimer’s Month in an effort to solicit evidence for ADRD DHTs from the broader scientific and digital health communities (September, 2023).

The combined literature search resulted in an initial dataset of 1,743 manuscripts; after screening we identified 153 eligible articles related to 117 unique DHTs. We reviewed and omitted 13 technologies that were clearly obsolete and discontinued, bringing the results from the literature to 102 DHTs. Project partners reviewed the complete list and made us aware of an additional 57 technologies, resulting in a potential total of 159 unique DHTs for ADRD assessment. Surveys were disseminated via email to technology developers of the additional technologies to request evidence so their technologies could be considered for inclusion; as of this writing, 42 survey submissions featuring 17 technologies were returned. Survey responses included peer-reviewed publications, conference poster and oral presentation materials, and documentation of regulatory approvals. After assessing all returned materials for eligibility as outlined in Table 1 , our total results included 172 pieces of evidence representing 106 unique DHTs. A list of the results of eligible manuscripts/evidence and the respective technologies therein is available in the supplementary material.

Populations Represented

Our results captured a wide variety of ADRD population descriptors as reported by study authors or DHT developers (Table 2 ). The classifications most represented include Mild Cognitive Impairment (MCI) in 39% of evidence records and 49% of technologies, followed by the general classification of Alzheimer’s disease indicated in 31% of evidence records and 40% of technologies.

Technology Types, Form Factors, and Health Concepts

Ambient (or non-wearable sensor technologies) are the most prevalent technology type, representing 61% of included DHTs and 68% of the evidence (Table 3 ). This category includes environmental or stand alone sensors as well as software and application-based technologies which are not tied to a given device. 83% of ambient technologies fall into the software and application category. Wearable sensor devices represent 32% of DHTs and 26% of evidence. Seven percent of technologies incorporate both wearable and ambient technologies. The most common form factors are software and applications designed for a tablet or smartphone (42% DHTs; 45% of evidence) and sensors worn on the body but not as a smartwatch (e.g. attached via a strap or brace) (19% DHTs; 16% of evidence). Cameras and contactless sensors are also strongly represented in the ambient category (collectively 13% DHTs; 14% evidence), while smartwatches represent a smaller portion of the results (8% DHTs; 5% evidence). Most studies feature commercially available DHTs (89% of evidence) though we included experimental/noncommercial DHTs if relevant to our population and concepts of interest (11% evidence). Our results also returned examples of “smart home” applications with a combination of different technology types designed to passively monitor life space mobility such as cameras, movement detecting radar, or pressure mats.

DHTs are classified into the health concepts of interest they assess, including but not limited to activities of daily living; mental health, neurocognitive function, neurological or sensory function, physical activity, and sleep (Table 4 ). The most frequent concept of interest is neurocognitive function with 43% of technologies and 51% of the evidence, but physical activity represents a larger portion of DHTs (48%) and is addressed in 42% of evidence. Measured outcomes as reported in included studies were analyzed to categorize the evidence into more specific health concepts. Memory is the concept of interest addressed most often as a primary focus of 26% of DHTs and 26% of evidence, but life space mobility, speech patterns and characteristics, gait and mobility, sleep, and several subdomains of memory and cognitive function are also well represented (Table 4 ).

V3, other evidence standards in action

The V3 framework ( 17 ) codifies best practices for evaluating verification, analytical validation, and clinical validation to determine whether DHTs are fit for purpose. Briefly, these processes evaluate whether sensor-based technologies and their algorithm(s) measure and interpret what they intend to measure, and provide metrics that are clinically or functionally meaningful in the stated context of use ( 17 ). To reflect these standards, we categorized evidence to indicate when it reports verification, analytical validation, clinical validation, and/or usability. Most of the current evidence reports validation: 34% of the evidence reports analytical validation while a majority (69%) reports evidence for clinical validation within ADRD populations. 19% percent of the evidence reports demonstrated usability or feasibility within ADRD populations. Just three manuscripts reported verification. These categories are not mutually exclusive; a single manuscript might report on multiple aspects.

To the best of our knowledge, this review is the first to broadly document the growing landscape of DHTs available for assessment within the ADRD space. DHTs focused on cognition and memory are unsurprisingly prevalent in our results. However, we identified several other concepts of interest in the literature, underscoring the versatility DHTs offer for holistic assessment of ADRD populations. When examining technology types, mobile or software applications are prevalent and their broad scope is notable. We find these technologies are being used by researchers and clinicians to assess multiple aspects of neurocognition (including several types of memory, attention, executive functioning, and processing speed); speech production and language characteristics; fine motor functioning; oculomotor behavior; sleep; gait, mobility, or balance; life space mobility dynamics; and emotional or other behavioral patterns. Given the ubiquity of smartphones and web-based options for assessment, these findings indicate a large capacity for sensitive and ongoing patient assessment or monitoring in clinical and real world settings, including the critical opportunity to reach patients not previously accessible to research or therapeutic settings. A majority (89%) of our results feature commercially available DHTs, emphasizing that a range of technological solutions are available and in use by clinicians and researchers even as additional development and innovation continues.

Biomarkers, early detection opportunities, and digital phenotyping

Our results indicate researchers are leveraging DHTs to identify digital biomarkers and behavioral changes that can provide early indicators of functional and cognitive changes in both clinical and remote settings. Examples include but are not limited to wearable headbands for in-home EEG assessment to monitor sleep, sophisticated analysis of speech patterns and vocal dynamics as captured by smartphone speakers, cameras tracking patterns in narrow applications (gaze/eye movement) as well as broad (behavioral) patterns in the home; and inertial sensors worn on the lower back, chest, arm, or leg to monitor mobility patterns. These technologies detect subtle functional and behavioral differences that can differentiate patients from healthy controls and discriminate between disease stages. When tablet or smartphone apps, wearables, and other DHTs are used in aggregate, the results can be quite illustrative, providing a “digital phenotype” ( 24 ) that captures a comprehensive in-situ portrait of someone’s daily functional and cognitive status, providing a better window into a patient’s emotional state, social patterns, and physical experiences to generate research insights and guide clinical care in ways that are meaningful to patients ( 25 ). “Smart home” applications show promise in this regard as well, with personalized and multimodal monitoring that might include cameras that track life space mobility paired with bed pressure mats to detect sleep patterns, restlessness, or agitation. When these technologies detect signals such as behavioral and activity changes, a digital phenotype can be established. Such setups are currently utilized in a variety of ways including discriminating between disease states ( 26 ), detecting agitation or apathy ( 27 ), unobtrusively monitoring response to therapeutics in care settings ( 28 ), and improving the selection of candidates for clinical research purposes ( 29 ).

Clinical research

The importance for understanding the landscape of ADRD-based DHTs is apparent when considering clinical research. Broadly, DHTs can improve trials by (a) reducing within-participant measurement noise ( 30 ), ultimately leading to improved statistical power, smaller trials ( 29 ), and faster paths to regulatory judgment of new therapies and (b) decentralizing assessments, enabling the participation of individuals located in more diverse geographical areas and therefore acquiring a more representative and diverse sample of the population under study ( 9 ). (For explication of this approach, see Sliwinski, 2008) ( 31 ). Although there is a recent example elsewhere in clinical research using a DHT as a primary clinical endpoint ( 32 ), this is not current practice in the ADRD space. However, the growing acceptance of DHTs as secondary endpoints in ADRD research ( 33 , 34 ) is slowly moving the field towards this possibility ( 35 , 36 ). Studies employ DHTs for monitoring response to treatment in a variety of ways, such as using actigraphy to discern impacts of Mevidalen on activity and sleep within Lewy Body dementia cohorts ( 37 , 38 ) or using smartwatches to detect suvorexant-induced changes in sleeping patterns for persons with Alzheimer’s experiencing insomnia ( 39 ).

Digital neuropsychology

The dominance of technologies assessing memory (short term, long term, working), executive function, attention, processing speed, verbal fluency, and visuospatial processing document an increasingly digital shift within neuropsychological assessment. Clinicians see value in the opportunity to assess functional status in real world settings ( 40 ) even as they grapple with concerns around ecological validity ( 25 , 41 ) due to variations in technology, computer literacy, environmental factors, and the presence or lack of supervision by a trained observer ( 41 , 42 ). While further research is needed to assuage these concerns, data continues to emerge illustrating that innovative digital assessment modalities can successfully discriminate between healthy controls and individuals in early stages of Alzheimer’s disease ( 43 ). Such DHTs provide clear advantages with regard to scalability and increasing access to patients for whom an in-person assessment may not be feasible ( 41 ), as well as the potential for real world and longitudinal evidence gathering ( 44 ) in populations where early detection is key. Many of the ambient technologies captured in this analysis were smartphone or tablet applications designed to analyze and interpret cognition or fine motor function to detect cognitive decline or discriminate between dementia states. Some examples include digital tasks testing aspects of cognition such as working memory, processing speed, or episodic memory ( 45 ); executive function ( 46 ); reaction time ( 47 ); speech or text patterns ( 48 , 49 ); or pressure of a digital pen( 50 ) on a device.

Wearables versus ambient sensors

Wearable sensors generally (32%), and smartwatches in particular (8%) were less represented in our landscape review than ambient technologies. Given their abundance and relative accessibility, wearable sensors can play an important role in the sensitive assessment of many ADRD-relevant measures, including mobility ( 51 ) (including but not limited to gait, life space pattern changes, and fall detection) and other biomarkers such as late-onset essential tremor ( 52 ) or heart rate variability ( 3 ). However, the lower proportion of wearables to ambient technologies may be a reflection of the versatility and advantages of the latter for dementia populations. For example, ambient sensors may be more appropriate for populations where memory or awareness concerns might make adherence with wearables a challenge. The aforementioned smart home possibilities with cameras, pressure sensors, and/or smart speakers/smartphones that detect changes in behavioral patterns or vocal biomarkers offer a powerful modality for real world continuous data collection while posing minimal burden on patients or caregivers.

Diagnostic classifications

Our results encompass a wide spectrum of dementia diagnoses and severity classifications. However, we note the prevalence of Alzheimer’s disease in our results compared to Frontotemporal dementias and Lewy Body dementia, as well as the prevalence of diagnoses like mild cognitive Impairment or general dementia as compared to results that specifically examined populations with moderate or advanced diagnoses. This suggests an opportunity for DHT developers and researchers to study additional uses and clinical validity within populations that are more narrowly defined within disease severity class, or in dementias other than Alzheimer’s disease.

Digital Measurement Products Library: A living resource

The digital health technology landscape evolves rapidly. Technologies from this review with peer-reviewed evidence published 2020-present are collated into the Library of Digital Measurement Products, an open access resource hosted by DiMe ( 53 ) for the clinical, research, and developer communities. While our landscape analysis included evidence published between 2003–2023 featuring DHTs that are both commercial and experimental, the library is a living resource intended to assist researchers and clinicians who may be considering a current and specific use case. Thus, it describes DHTs that are commercially available on the market at the time of entry into the database, and is restricted to peer-reviewed evidence published from 2020-present. Evidence is tagged according to the study type by which it is reported in the published literature as verification, analytical validation, clinical validation, or usability ( 17 ). Categorical fields are filterable so the end user can sort and view evidence according to a specific technology or technology type, therapeutic area or concept of interest, or by reported evidence type. This library aligns with the mission of the Digital Health Measurement Collaborative Community ( 13 , 14 ) to share knowledge and resources to advance digital medicine and ultimately improve patient lives; we encourage the wider ADRD community to join our collective efforts to ensure diverse evidence-supported DHTs are represented in this important resource. A link to submit evidence for potential inclusion into the library is available to the public on DiMe’s Library of Digital Measures Products web page ( 53 ); beginning mid-2024, the library will be updated quarterly via review of community submissions, revisiting of the published literature, and removal of outdated evidence.

Limitations

While our results provide a broad overview of DHTs for ADRD assessment across 20 years of literature, we intentionally excluded brand-name identifiers from our search strings to avoid bias by disproportionately representing some market technologies over others. Additionally, we omitted search terms specific to Parkinson’s disease dementia because it has differentiating features from other dementias, and therefore will be the focus of a similar exercise in future research. Due to this intentional limiting of some search terms, we do not claim the search results to be exhaustive. As we conducted this exercise to aggregate DHTs and their uses within ADRD, with a focus on extracting technologies rather than conducting a formal appraisal of the literature, we report these findings as a technology landscape analysis rather than a traditional systematic review.

Lastly, members of the DiMe working group made the authorship team aware of additional technologies which were not identified/discovered via the literature search. While this carries a risk of bias (primarily that some additional technologies were presumably overlooked due to being unknown to project partners), we considered that the benefits of greater inclusion outweighed this potential drawback. We reached out to solicit supporting evidence for these, but received evidence back for a small portion. Consequently, many of the technologies identified during partner review are not included in this analysis, as we lacked the associated evidence necessary to report on them.

DHTs show great promise for ADRD populations by enabling objective, continuous, and repeatable measurements of functioning and symptoms in a range of settings. Ambient, application-based, and wearable technologies offer vast real world and longitudinal evidence generation possibilities, as well as the opportunity to take traditional neuropsychological and neurocognitive assessment out of the clinic or laboratory and into homes and care settings. They offer additional information to facilitate clinical decision making, and provide opportunities for clinical research to identify earlier signals of disease onset, monitor disease trajectory, or detect response to therapeutic treatment at a time when demand is increasing for precision medicine that better identifies and targets appropriate candidates for care and intervention, particularly in the prodromal or earliest stages ( 54 , 55 ). These technologies continue to elucidate insights about domains such as cognitive function, sleep, mobility, language changes, and social and behavioral trends which will prove invaluable alongside traditional dementia research and management. This review confirms the multifaceted uses for and significant potential of DHTs as clinicians and researchers seek clarity and insights beyond the reach of traditional assessment modalities.

Abbreviations

• Alzheimer’s disease

Alzheimer’s disease and related dementias

Digital Health Measurement Collaborative Community

Digital health technology

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Acknowledgments

We appreciate the support of our collaborating partners and experts who comprise the DATAcc by DiMe ADRD Project working group and supported this manuscript: Abbvie; Altoida, Alzheimer’s Drug Discovery Foundation, Aural Analytics, Biogen, BioSensics, Boston University, Cambridge Cognition, Cogniant Pte Ltd, Cognito Therapeutics, Cogstate, Cumulus Neuroscience, Eisai, Eli Lilly & Company, Gates Ventures, ki:elements, Koneksa, Linus Health, Luca Health, Medidata, Merck, Northwestern University, Oregon Health & Science University, Roche, Sage Bionetworks, VivoSense, Winterlight Labs.

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Cogniant Pte Ltd, Singapore and ClinMed LLC, Dayton, NJ, USA

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Author Contributions: All authors contributed to the conceptual development of this manuscript. All authors have approved the final submitted version and agree to be accountable for all aspects of the work presented here.

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Conflict of interest: SAL is an employee of the Digital Medicine Society; ES is an employee of Altoida and holds company stock; SLB is an employee of VivoSense, Inc; KB is an employee of Merck & Co and Co-Chair of Mobile in Clinical Trials Conference; JD is an employee of Cumulus Neuroscience, holds company stock, & is coauthor on a pending patent with other Cumulus Neuroscience employees; CFA receives consulting income from Cogniant Pte Ltd.; JCG is an employee of the Digital Medicine Society; AH is an employee of Eli Lilly & Co. and holds company stock; AJ is an employee of Linus Health, Inc. and is listed as an inventor on pending patents on digital biomarkers of cognition and digital assessments for early diagnosis of dementia; RSF is an employee of Eisai Farmaceutica SA; PF is an employee of the Digital Medicine Society, reports consulting income from Sarepta, IQVIA, Clarivate, Open Health, has a leadership or fiduciary role with International Society of Quality of Life, and is president of consulting company SeeingTheta.

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Lott, S.A., Streel, E., Bachman, S.L. et al. Digital Health Technologies for Alzheimer’s Disease and Related Dementias: Initial Results from a Landscape Analysis and Community Collaborative Effort. J Prev Alzheimers Dis (2024). https://doi.org/10.14283/jpad.2024.103

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DOI : https://doi.org/10.14283/jpad.2024.103

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Research team develops searchable database for Alzheimer's research

by Ohio State University Medical Center

A searchable database is now ready to help study Alzheimer's disease.

Neuroscience and biomedical informatics researchers at The Ohio State University Wexner Medical Center and College of Medicine created the comprehensive, user-friendly repository.

The free database—known as ssREAD —is outlined in a manuscript published online in Nature Communications .

Alzheimer's disease is the most common cause of dementia, accounting for up to 80% of cases. An estimated 6.7 million Americans who are age 65 and older are living with Alzheimer's dementia today, according to the Alzheimer's Association's 2023 Alzheimer's disease facts and figures report.

This database will help researchers study the pathology of Alzheimer's disease. Pathology examines the cause, development, structural/functional changes and natural history associated with diseases.

Molecular signatures underlying Alzheimer's disease pathology have been increasingly explored through single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) and spatial transcriptomics.

"These technologies have cast fresh light on the exploration of Alzheimer's disease pathogenesis and sex difference at the cellular and molecular levels. Our ssREAD repository offers a broader spectrum of Alzheimer's disease-related datasets, with an optimized analytical pipeline and improved usability," said study co-corresponding author Hongjun "Harry" Fu, Ph.D., assistant professor of neuroscience at Ohio State.

The database encompasses 277 integrated datasets from 67 Alzheimer's disease-related scRNA-seq and snRNA-seq studies, totaling 7,332,202 cells. The repository also includes 381 spatial transcriptomics samples from 85 human and mouse studies.

• Detailed annotations including cell types and spatial layers
• Differential gene expressions and functional enrichment analysis
• Spatially variable genes and deconvolution with single-cell datasets

Interactive visualizations

User-friendly web server to provide comprehensive analysis interpretations and filters support multiple selections

• Scatter plots for clusters, cell types, and spatial layers
• Feature plots and violin plots for gene expression profile
• Real-time gene set enrichment analysis

"We are closing the gap for researchers by creating this specialized database. Integrating these diverse datasets and conditions will be invaluable for researchers studying the complex landscape of Alzheimer's disease," said Qin Ma, Ph.D., professor in Ohio State's department of biomedical informatics .

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Study Identifies Genetic Variant as a Clear Cause of Alzheimer's—Does This Mean You Should Get Tested?

Fact checked by Nick Blackmer Fact checked by Nick Blackmer

• New research suggests that having two copies of the gene variant APOE4 could be a cause of developing Alzheimer’s.
• The study also found that people with two copies of APOE4 were more likely to develop Alzheimer’s earlier in life.
• Experts don't typically advise genetic testing for Alzheimer's for most people, and a study author said the new research doesn't change current recommendations.

Recent research suggests that some Alzheimer’s cases can be traced back to a direct genetic cause.

Currently, most cases of Alzheimer’s don't have an identifiable underlying cause. Still, scientists have long known that inheriting a copy of a gene variant called APOE4 can elevate the chances of a diagnosis. People with two copies, who make up 2 to 5% of the general population, are at even higher risk. 

Now, researchers are proposing that having two copies of APOE4 doesn’t just raise the odds of developing the disease but can, in fact, cause it. 

“This expands our understanding to encompass 15 to 20% of cases where we can identify a genetic cause,” Juan Fortea, PhD , who led the study at the Sant Pau Research Institute in Barcelona, Spain, told Health . “This is crucial as it opens new avenues for specific research and interventions, enhancing our grasp on the disease’s underlying mechanisms.”

The new findings, published in the journal Nature Medicine , also mean more people could receive an Alzheimer’s diagnosis before they begin to show any symptoms. Medical experts say this research will hopefully spur the development of treatments and kickstart targeted clinical trials focused on this population.

“Our findings represent more than scientific progress,” Fortea said. “They are a step towards translating hope into tangible strategies for those affected by Alzheimer's.”

Here’s how the scientists made their discovery, what it could mean for Alzheimer’s treatment, and whether experts advise testing to see if you have the genetic variant.

A New Genetic Disorder

Researchers analyzed data from 3,297 brains donated for medical research and 10,000 people participating in U.S. and European Alzheimer’s studies.

They found that 273 people had two copies of APOE4. Of those, nearly all showed signs of Alzheimer’s in their brains. The researchers concluded that having two copies of APOE4 should now be considered a genetic form of Alzheimer’s.

The team also found that patients developed Alzheimer’s pathology relatively young .

By age 55, participants with two APOE4 copies were accumulating more amyloid, a protein that forms plaques in the brain that signal Alzheimer’s, than those with just one copy of another form of APOE—the APOE3 allele. By 65, almost all had abnormal levels of amyloid. And many started developing symptoms of Alzheimer’s at age 65, younger than most people without the APOE4 variant.

“The study beautifully demonstrates that having two copies of the APOE4 gene predictably leads to pathological changes in the brain in almost every carrier,” Jim Ray, PhD , director of the Belfer Neurodegeneration Consortium at MD Anderson Cancer Center who was not involved in the study, told Health . 

Fortea acknowledged the study had notable limitations, including that almost all participants were White. Because the risk associated with APOE varies across different ethnic backgrounds, the findings might not be universally applicable.

Implications for Treatment

Ray and other experts said that the research could be a catalyst for the development of new drugs to treat people with two copies of the gene variant—both before and after they experience symptoms.

“This study argues strongly that we need therapeutics targeting the APOE4 gene for the millions of people who are at risk for AD,” he said.

No cure exists for Alzheimer’s, but some medications can temporarily improve symptoms. 

One of the more common prescriptions is Leqembi, which works to break apart some of the amyloid in the brain. Experts have been hesitant to widely prescribe the drug, however, because it carries an FDA-required black-box warning on the label that “serious and life-threatening events” like bleeding and swelling in the brain can occur, specifically in people with two copies of APOE4. 

“We are at the threshold of a new era with the advent of disease-modifying treatments, which holds significant promise for those with genetic markers linked to Alzheimer’s,” Fortea said.

Should You Get Genetic Testing?

The new study raises the question whether asymptomatic people should get tested to determine whether they have two copies of APOE4.

People whose parents were both diagnosed with Alzheimer’s relatively early—most likely in their 60s—are most likely to carry two APOE4 genes.

Currently, genetic tests aren’t routinely used in clinical settings to diagnose or predict the risk of developing Alzheimer’s. Many experts don’t advise it because of the complexities involved in interpreting the results. 

Fortea said she doesn’t think the new study should change anything regarding testing recommendations.

“At this stage, our findings do not advocate for changes in testing practices for Alzheimer’s,” Fortea said. “More research is needed, particularly in developing preventive treatments and accurately assessing risk, before we can offer concrete recommendations for genetic testing or counseling in the context of these findings.”

If you are curious about whether you have one or two copies of the APOE4 gene or concerned that you might, consult a doctor or genetic counselor about whether testing might be right for you.

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