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Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency event-related potential (ERP) component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage AD. Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using principal components analysis. C145 amplitudes and spatial distributions were compared among controls, AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the efficacy and safety of aripiprazole treatment for psychotic symptoms associated with Alzheimer disease (AD). METHODS: In this parallel group, randomized, double-blind, placebo-controlled, flexible-dose trial, institutionalized subjects with AD and psychotic symptoms were randomized to aripiprazole (n = 131) or placebo (n = 125) for 10 weeks. The aripiprazole starting dose was 2 mg/day, and could be titrated to higher doses (5, 10, and 15 mg/day) based on efficacy and tolerability. RESULTS: No significant differences in mean change [2 x SD] from baseline between aripiprazole (mean dose approximately 9 mg/day at endpoint; range = 0.7-15.0 mg) and placebo were detected in the coprimary efficacy endpoints of Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) Psychosis score (aripiprazole, -4.53 [9.23]; placebo, -4.62 [9.56]; F = 0.02, df = 1, 222, p = 0.883 [ANCOVA]) and Clinical Global Impression (CGI)-Severity score (aripiprazole, -0.57 [1.63]; placebo, -0.43 [1.65]; F = 1.67, df = 1, 220, p = 0.198 [ANCOVA]) at endpoint. However, improvements in several secondary efficacy measures (NPI-NH Total, Brief Psychiatric Rating Scale Total, CGI - improvement, Cohen-Mansfield Agitation Inventory and Cornell Depression Scale scores) indicated that aripiprazole may confer clinical benefits beyond the primary outcome measures. Treatment-emergent adverse events (AEs) were similar in both groups, except for somnolence (aripiprazole, 14%; placebo, 4%). Somnolence with aripiprazole was of mild or moderate intensity, and not associated with accidental injury. Incidence of AEs related to extrapyramidal symptoms was low with aripiprazole (5%) and placebo (4%). CONCLUSIONS: In nursing home residents with AD and psychosis, aripiprazole did not confer specific benefits for the treatment of psychotic symptoms; but psychological and behavioral symptoms, including agitation, anxiety, and depression, were improved with aripiprazole, with a low risk of AEs. [ABSTRACT FROM AUTHOR]

OBJECTIVES: 'Depression of Alzheimer's Disease' (dAD) is a common complication of Alzheimer's disease and is increasingly recognized as a syndrome with a clinical presentation differing from major depression. Criteria for the diagnosis of dAD have been proposed previously. METHODS: This paper presents these criteria in operationalized format designed to be accessible for clinical use. Four cases are discussed that demonstrate the use of these criteria and illustrate important differences between dAD and major depression. RESULTS: The dAD criteria are broader than DSM-IV criteria for Major Depressive Episode and incorporate caregiver input. CONCLUSIONS: Given the differences between dAD and major depression diagnoses, it is important to assess the efficacy of treatments for dAD. Depression in Alzheimer's Disease-2 (DIADS-2) is a controlled trial of dAD treatments that will also assess the validity of these criteria. [ABSTRACT FROM AUTHOR]

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer's disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to American Aging Association.)

Objectives: Among participants with Alzheimer's disease (AD) we estimated the minimal clinically important difference (MCID) in apathy symptom severity on three scales., Design: Retrospective anchor- and distribution-based analyses of change in apathy symptom scores., Setting: Apathy in Dementia Methylphenidate Trial (ADMET) and ADMET 2 randomized controlled trials conducted at three and ten clinics specialized in dementia care in United States and Canada, respectively., Participants: Two hundred and sixty participants (60 ADMET, 200 ADMET 2) with clinically significant apathy in Alzheimer's disease., Measurements: The Clinical Global Impression of Change in Apathy scale was used as the anchor measure and the MCID on the Neuropsychiatric Inventory - Apathy (NPI-A), Dementia Apathy Interview and Rating (DAIR), and Apathy Evaluation Scale-Informant (AES-I) were estimated with linear mixed models across all study visits. The estimated thresholds were evaluated with performance metrics., Results: Among the MCID was a decrease of four points (95% CI: -4.0 to -4.8) on the NPI-A, 0.56 points (95% CI: -0.47 to -0.65) on the DAIR, and three points on the AES-I (95% CI: -0.9 to -5.4). Distribution-based analyses were largely consistent with the anchor-based analyses. The MCID across the three measures showed ∼60% accuracy. Sensitivity analyses found that MMSE scores and apathy severity at baseline influenced the estimated MCID., Conclusions: MCIDs for apathy on three scales will help evaluate treatment efficacy at the individual level. However, the modest correspondence between MCID and clinical impression of change suggests the need to consider other scales.

Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT 1A and dopamine D 2 receptor agonist activity and serotonin 5-HT 2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials., Competing Interests: Disclosures E.D.C. reports personal fees from Genomadix Inc and a grant to her institution from Alzheon. A.P.P. reports personal fees from Acadia Pharmaceuticals, Athira, BMS, Cognitive Research Corp, Eisai, IQVIA, Lundbeck, Novartis, ONO Pharmaceuticals, WCG, WebMD, and Xenon; and grants to his institution from Alector, Athira, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and DOD. He is a member of the Scientific Advisory Board of Alzheon. D.L. and I.M.A. declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E ( APOE ) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD., Methods: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes., Results: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024., Discussion: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population., Highlights: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E ( APOE ) ε4/ε4 genotype.The enrolled early AD population ( N  = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects., Competing Interests: Drs. Susan Abushakra, Aidan Power, Earvin Liang, J. Patrick Kesslak, John A. Hey, Susan Flint, Rosalind McLaine, and Martin Tolar are employees and own stocks or stock options in Alzheon Inc.; Drs. Anton P. Porsteinsson, Marwan Sabbagh, and Merce Boada are advisors to several companies developing AD drugs. Drs. David Watson, Emer MacSweeney, and Merce Boada are investigators in the Phase 3 study and are active investigators in multiple AD clinical trials with various mechanisms of action. Author disclosures are available in the supporting information., (© 2024 Alzheon, Inc. and The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia., Methods: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist., Results: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period., Conclusions: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment., (© 2024 John Wiley & Sons Ltd.)

Introduction: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD., Areas Covered: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aβ 42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau 181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion., Expert Opinion: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

Objective: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate., Design: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori., Setting: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial., Participants: Alzheimer's disease patients with clinically significant apathy., Measurements: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A)., Results: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale., Conclusion: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive., Methods: A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors., Results: Costs were not significantly different between groups whether the cost of methylphenidate was excluded ( F (2,330) = 0.626, η p 2 = 0.004, p = 0.535) or included ( F (2,330) = 0.629, η p 2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction ( F (2,330) = 7.525, η p 2 = 0.044, p < 0.001)., Discussion: Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer's disease while considering the burden on the healthcare system.

Introduction: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study., Methods: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores., Results: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria ( P = 0.044) and appetite/eating disorders ( P = 0.014); however, these findings were not considered significant., Discussion: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms., Competing Interests: Dr. Brawman‐Mintzer receives grant funding from the National Institute on Aging, Merck, Alzheimer's Trials Research Institute and Alzheimer's Cooperative Trials Consortium, and the Department of Defense. Dr. Brawman‐Mintzer has served as a steering committee member for the Alzheimer's Disease Cooperative Study and as an associate steering committee member with the Alzheimer's Clinical Trials Consortium. Dr. Brawman‐Mintzer has received payment or honoraria from Medscape. Dr. Clark reports grants to her institution for clinical trials from Alzheon and Biogen. Dr. Lanctôt reports grants from Alzheimer's Association (PTC‐18‐543823, PTCG‐20‐ 700751), Alzheimer Society of Canada, Alzheimer's Drug Discovery Foundation (Grant No: 2016354), Canadian Institutes Health Research (PJ2‐179752, PJT‐183584), National Institute on Aging (R01AG046543), and Weston Brain Institute; consulting fees from BioXcel Therapeutics, Bright Minds, Cerevel Therapeutics, Eisai Co. Ltd, Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck, Novo Nordisk, Praxis Therapeutics, Sumitomo Pharma Co. Ltd; stock options from Highmark Interactive outside the submitted work. Krista Lanctôt is the Bernick Chair in Geriatric Psychopharmacology of Sunnybrook Health Sciences Centre and University of Toronto's Temerty Faculty of Medicine. Dr. Lerner receives research grant support from the National Institutes of Health and National Institute on Aging (P30AG072959), Alzheimer's Clinical Trials Consortium, the Elisabeth S. Prentiss Foundation. He receives honoraria for consulting from Premier Inc (PINC AI Applied Sciences). He has received book royalties from Elsevier. He is a steering committee member of the Alzheimer's Clinical Trials Consortium. Dr. Jacobo Mintzer is a consultant and Governance Committee Member for AARP's Global Council on Brain Health and a consultant and Scientific Advisor for AARP's Staying Sharp Scientific Advisory Committee. He is a consultant for ACADIA, AiOmed, Corium, Exciva, Genentech (affiliate of F. Hoffmann‐La Roche Ltd), Ironshore Pharmaceuticals, Lundbeck, Praxis Bioresearch, and Sygnature Discovery. Dr. Mintzer is a Steering Committee Member for the Alzheimer's Clinical Trials Consortium, Alzheimer's Disease Cooperative Study, and the Elder Court. He is a Board Member for the Alzheimer's Association, SC Chapter and the Technology Accelerator Company as well as an Association Member of the International Psychogeriatric Association. He is a Scientific Advisory Board Member for Exciva and Advisory Board Member for ACADIA. Dr. Mintzer is a stockholder and the VP for Clinical Affairs for NeuroQuest, a majority owner of Biopharma Connex, and a majority partner for Recruitment Partners. Dr. Mintzer has received payment or honoraria from ACADIA. He is receiving support for specific clinical trials from Cerevel Therapeutics, LLC, Eisai Inc., Eli Lilly and Company, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, the National Institute on Aging, the National Institutes of Health, and the National Endowment for the Arts. Dr. Mintzer has received support for attending meetings and/or travel from AARP Global Council on Brain Health (GCBH), AiOmed, and Alzheimer's Clinical Trials Consortium. Finally, he has served as a DSMB member for NAB‐It: Nabilone for Agitation Blinded Intervention Trial. Dr. Padala receives support for his time from the Department of Veterans Affairs and the National Institutes of Health. Dr. Perin received grant support for the present manuscript from the National Institutes of Health (Grant R01AG046543). Dr. Rosenberg has received research grants from the National Institute on Aging, Alzheimer's Association, Alzheimer's Clinical Trials Consortium, Alzheimer's Trials Research Institute and Alzheimer's Cooperative Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer's Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from consulting for GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Biogen, MedaCorp, ExpertConnect, and HMP Global. He participates on an advisory board for Synaptogenix. He has received honoraria for presentations from Medscape and Neurology Week, and has received support for travel for a consultation meeting from Lundbeck. Dr. David Shade received grant support for the present manuscript from the National Institutes of Health. Dr. van Dyck serves as a scientific advisor for Eisai, Roche, Ono, and Cerevel and reports grant support for clinical trials from Biogen, Biohaven, Cerevel, Eisai, Eli Lilly, Genentech, Janssen, Roche, and UCB. He also participates as a member of the Medical and Scientific Advisory Group for the Alzheimer's Association. Dr. Porsteinsson reports DSMB membership fees from Acadia, Cadent, Cognitive Research Corp, Functional Neuromodulation, Neurim, Novartis, and Tetra Discovery Partners; consulting fees from Athira, Avanir, Biogen, BioXcel, Eisai, Grifols, IQVIA, Lundbeck, Maplight Therapeutics, Merck, ONO Pharmaceuticals, Pfizer, and Toyama; grants for clinical trials from the National Institute on Aging, National Institute on Mental Health, the Department of Defense, Alector, AstraZeneca, Athira, Avanir, Biogen, Biohaven, Cassava, Eisai, Eli Lilly, Genentech/Roche, Janssen, Merck, Novartis, Toyama, and Vaccinex outside the submitted work. Dr. Herrmann declares no conflicts of interest. Susie Sami declares no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is a common and distressing NPS, without safe and effective treatments. Nonpharmacological interventions are first line treatment, but not effective or appropriate for every patient. Current pharmacological treatments of agitation in AD include off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite prevalent use, efficacy and safety concerns remain., Areas Covered: Better understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. Comprehensive search of ClinicalTrials.gov was completed from January 2017 to February 2023 using the search terms "Alzheimer's Disease" and "Agitation". Subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin., Expert Opinion: Clinical trials utilize both novel and repurposed agents for agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel development of agitation in AD, use of enahanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we advance closer to safe and efficacious treatment options for agitation in AD.

Background: Neuropsychiatric symptoms (NPS) in mild cognitive impairment (MCI) cause distress to patients and caregivers, and accelerate progression to dementia. Transcranial direct current stimulation (tDCS) is a promising non-invasive treatment for NPS., Objective/hypothesis: This pilot study assessed behavioral and neural effects of a 4-week anodal tDCS intervention targeting left sensorimotor cortex (LSMC: left precentral/postcentral gyri) during visual attention (compared to online sham tDCS), in 40 older adults (24 females, mean age = 71) with MCI., Methods: A phase 0 double-blinded randomized control trial was conducted. NPS (patient-reported mood symptoms plus a caregiver-reported questionnaire) and fMRI were measured at baseline and immediately post-intervention., Results: Generalized Estimating Equations found no significant group by time interactions for either NPS measure. However, there was evidence of decreased patient-reported NPS (Wald's χ 2  = 3.80, p = .051), decreased LSMC activation during visual attention (Wald's χ 2  = 2.93, p = .087), and increased LSMC-amygdala resting-state functional connectivity (rsFC; Wald's χ 2  = 3.13, p = .077) in intervention group from pre-to post-intervention. Decrease in LSMC activation (Wald's χ 2  = 9.20, p = .002) and increase in LSMC-amygdala rsFC (Wald's χ 2  = 4.72, p = .030) related to decreased patient-reported NPS. Increased positive valence across sessions was significantly associated with intervention-related NPS improvement (Wald's χ 2  = 22.92, p < .001). There were no findings for caregiver-reported NPS. Effects were stronger for left postcentral compared to left precentral gyrus., Conclusion: We found tentative evidence that tDCS applied to LSMC during visual attention in older adults with MCI improved NPS via changes in LSMC activation and LSMC-amygdala rsFC, suggesting improved emotion regulation. Patient-reported NPS was more sensitive to these changes than caregiver-reports, and effects were strongest for left postcentral gyrus. Follow-up studies should perform precise mechanistic investigation and efficacy testing., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality., Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease., Design, Setting, and Participants: This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included., Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo., Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life., Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups., Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease., Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.

Study Objectives: To examine in a subsample at the screening phase of a clinical trial of a β-amyloid (Aβ) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer's disease (AD)., Methods: Overall, 26 Aβ-positive (Aβ+) and 33 Aβ-negative (Aβ-) cognitively unimpaired participants (mean age = 71.3 ± 4.6 years, 59% women) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, respectively, wore actigraphs for 5.66 ± 0.88 24-hour periods. We computed standard sleep parameters, standard RAR metrics (mean estimating statistic of rhythm, amplitude, acrophase, interdaily stability, intradaily variability, relative amplitude), and performed a novel RAR analysis (function-on-scalar regression [FOSR])., Results: We were unable to detect any differences between Aβ+ and Aβ- participants in standard sleep parameters or RAR metrics with our sample size. When we used novel FOSR methods, however, Aβ+ participants had lower activity levels than Aβ- participants in the late night through early morning (11:30 pm to 3:00 am), and higher levels in the early morning (4:30 am to 8:30 am) and from midday through late afternoon (12:30 pm to 5:30 pm; all p < .05). Aβ+ participants also had higher variability in activity across days from 9:30 pm to 1:00 am and 4:30 am to 8:30 am, and lower variability from 2:30 am to 3:30 am (all p < .05)., Conclusions: Although we found no association of preclinical AD with standard actigraphic sleep or RAR metrics, a novel data-driven analytic method identified temporally "local" RAR alterations in preclinical AD., (© The Author(s) 2021. Published by Oxford University Press on behalf of Sleep Research Society.)

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease is a progressive, irreversible neurodegenerative disease impacting cognition, function, and behavior. Alzheimer's disease progresses along a continuum from preclinical disease, to mild cognitive and/or behavioral impairment and then Alzheimer's disease dementia. Recently, clinicians have been encouraged to diagnose Alzheimer's earlier, before patients have progressed to Alzheimer's disease dementia. The early and accurate detection of Alzheimer's disease-associated symptoms and underlying disease pathology by clinicians is fundamental for the screening, diagnosis, and subsequent management of Alzheimer's disease patients. It also enables patients and their caregivers to plan for the future and make appropriate lifestyle changes that could help maintain their quality of life for longer. Unfortunately, detecting early-stage Alzheimer's disease in clinical practice can be challenging and is hindered by several barriers including constraints on clinicians' time, difficulty accurately diagnosing Alzheimer's pathology, and that patients and healthcare providers often dismiss symptoms as part of the normal aging process. As the prevalence of this disease continues to grow, the current model for Alzheimer's disease diagnosis and patient management will need to evolve to integrate care across clinical disciplines and the disease continuum, beginning with primary care. This review summarizes the importance of establishing an early diagnosis of Alzheimer's disease, related practical 'how-to' guidance and considerations, and tools that can be used by healthcare providers throughout the diagnostic journey., Competing Interests: AP reports personal fees from Acadia Pharmaceuticals, Alzheon, Avanir, Biogen, Cadent Therapeutics, Eisai, Functional Neuromodulation, MapLight Therapeutics, Premier Healthcare Solutions, Sunovion, and Syneos; grants from Alector, Athira, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, and Vaccinex. RI has nothing to disclose. MS reports personal fees from Alzheon, Athira, Biogen, Cortexyme, Danone, Neurotrope, Regeneron, Roche-Genentech, and Stage 2 Innovations; stock options from Brain Health Inc, NeuroReserve, NeuroTau, Neurotrope, Optimal Cognitive Health Company, uMethod Health, and Versanum Inc. Additionally, he has intellectual property rights with Harper Collins. SK and IR report employment with Biogen.

Background: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver., Objective: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored., Methods: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation., Results: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%)., Conclusion: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Hippocampal volume (HV) and cortical thickness are commonly used imaging biomarkers in Alzheimer's disease (AD) trials, and may have utility as selection criteria for enrichment strategies. Atrophy rates of these measures, in the high-risk apolipoprotein E (APOE) ε4/ε4 homozygous AD subjects are unknown., Methods: Data from Alzheimer's Disease Neuroimaging Initiative (ADNI-1) and a tramiprosate trial were analyzed in APOE ε4/ε4 and APOE ε3/ε3 subjects with mild cognitive impairment (MCI) or mild AD. Magnetic resonance imaging (MRI) data were centrally processed using FreeSurfer; total HV and composite average cortical thickness were derived and adjusted for age, head size, and education. Volumetric changes from baseline were assessed using Boundary Shift Integral, and correlated with cognitive changes., Results: APOE ε4/ε4 MCI subjects showed significantly higher % HV atrophy and cortical thinning at 12 months (4.4%, 3.1%, n = 29) compared to APOE ε3/ε3 subjects (2.8%, 1.8%, n = 93) and similarly in mild AD (7.4%, 4.7% n = 21 vs 5.4%, 3.3% n = 29). Differences were all significant at 24 months. Over 24 months, HV atrophy and cortical thinning correlated significantly with Alzheimer's Disease Assessment Scale-Cognitive subscale worsening in APOE ε4/ε4 MCI subjects, but not in mild AD., Discussion: Correlation of volumetric measures to cognitive change in APOE ε4/ε4 subjects with early AD supports their role as efficacy biomarkers. If confirmed in a Phase 3 trial with ALZ-801 (pro-drug of tramiprosate) in APOE ε4/ε4 early AD subjects, it may allow their use as surrogate outcomes in future treatment or prevention trials in AD., Competing Interests: Dr. Susan Abushakra serves as the chief medical officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. Martin Tolar serves as the founder, president, and chief executive officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. John A. Hey serves as the chief scientific officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. Aidan Power serves as a vice president at Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. Anton Porsteinsson receives research support from the National Institutes of Health and U.S. Department of Defense. He also receives grants from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, Janssen, Novartis, Merck, and Toyama. He receives personal fees from Acadia Pharmaceuticals, Avanir, BioXcel, Eisai, Functional Neuromodulation, Grifols, Lundbeck, Merck, Neurim Pharmaceuticals, Pfizer, Tetra Discovery Partners, and Toyama. Dr. Marwan Sabbagh receives research support from the NIH and the Keep Memory Alive Foundation. He has consulting agreements with Allergan, Biogen, Bracket, Cortexyme, Grifols, Sanofi, Neurotrope, and Roche‐Genentech. He has ownership interest in Brain Health Inc., Versanum Inc., Neurotrope Inc., and uMethod Health. Drs. Joyce Suhy, Luc Bracoud, Joel Schaerer, and David Scott serve as full‐time employees of Bioclinica Inc. and have no competing interest in Alzheon Inc., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Competing Interests: Dr. Porsteinsson reports personal fees from Acadia Pharmaceuticals, Avanir, Cadent Therapeutics, Eisai, Functional Neuromodulation, and Tetra Discovery Partners; grants to his institution from Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, Novartis, outside of the submitted work. Dr. Clark has nothing to disclose.

Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals' cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation., Competing Interests: MB is affiliated with the Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; and with the Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain. Private research funding sources include Grifols SA; Caixabank S.A.; Life Molecular Imaging; Araclon Biotech; Laboratorios Echevarne; Festival Castell Paralada; Bonpreu/Esclat; and Famila Carbó. Public grants include those from Instituto de Salud Carlos III. Ministerio de Salud. Gobierno de España; Dirección General de Farmacia. Ministerio de Salud. Gobierno de España; and European Commission:H2020 program, Innovative Medicine Initiative (IMI-2); and ERA-NET NEURON program, European Marie Sklodowska Curie. Advisory work includes that for Araclon Biotech, Biogen, Bioibérica, Eisai, Grifols, Lilly, Merck, Nutricia, Roche, Oryzon, Schwabe Farma, Servier, and Kyowa Kirin. BD is affiliated with the Institute of Memory and Alzheimer’s Disease (IM2A), Department of Neurology, Salpêtrière Hospital, AP-HP, Sorbonne-Université, Paris, France. JI is affiliated as an Assistant Professor-Adjunct (Group1) with the Department of Family Practice at Queen’s University. She was also a panelist for Hoffman-La Roche Limited, Ottawa, on an Alzheimer’s Disease Panel. She is involved with the Canadian Consortium on Neurodegeneration in Aging (CCNA), Extension Study as a Co- Investigator and Research Coordinator. AI received lecture fees from Eisai, Janssen, Otsuka, Eli Lilly, MSD, Chugai-Roche, Daiichi-Sankyo, Alnylam, Takeda, UCB, Ono, Integra Japan, IQVIA, Fuji Rebio, Biogen, and advisory fees from Janssen during the past three years. AP reports personal fees from Acadia Pharmaceuticals, Functional Neuromodulation, Neurim Pharmaceuticals, Grifols, Eisai, BioXcel, Tetra Discovery Partners, and Merck; grants from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Janssen, Genentech/Roche, Novartis, Merck, as well as funding from NIA, NIMH, DOD. KLP receives grant funding from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Global Brain Health Institute, and Quest Diagnostics. BV has consultancy and research grants from Roche, Biogen, EISAI, Nestle, Lilly, Cerecin, and Merck. HH is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s and Dementia; during the past three years he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. He is co-inventor in the following patents as a scientific expert and has received no royalties: In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300; In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463; In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553; CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921. AV is an employee of Eisai Inc. and received lecture honoraria from Roche, MagQu LLC, and Servier.

Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user's behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future., Competing Interests: MNS Royalty: HarperCollins, Stock: uMethod Health, Brain Health, Inc, Optimal Cognitive Health Company, M3 Biosciences, Versanum, NeuroReserveAlzheon and Athira, Speakers Bureau: Peerview and Medscape and HWP, Consultant: Biogen, Bracket/Signant, Neurotrope, Cortexyme, Roche, Grifols, Sanofi, Regeneron, Eisai, Neuronix, Acadia. MB is affiliated with the Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; and with the Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain. Private research funding sources include Grifols SA; Caixabank S.A.; Life Molecular Imaging; Araclon Biotech; Laboratorios Echevarne; Festival Castell Paralada; Bonpreu/Esclat; and Famila Carbó. Public grants include those from Instituto de Salud Carlos III. Ministerio de Salud. Gobierno de España; Dirección General de Farmacia. Ministerio de Salud. Gobierno de España; and European Commission:H2020 program, Innovative Medicine Initiative (IMI-2); and ERA-NET NEURON program, European Marie Sklodowska Curie. Advisory work includes that for Araclon Biotech, Biogen, Bioibérica, Eisai, Grifols, Lilly, Merck, Nutricia, Roche, Oryzon, Schwabe Farma, Servier, and Kyowa Kirin. PMD has received research grants (through Duke University) from Avid, Lilly, Neuronetrix, Avanir, Bauch, Alzheimer’s Drug Discovery Foundation, Cure Alzheimer’s Fund, Wrenn Trust, DOD, ONR, and NIH. PMD has received speaking or advisory fees from Anthrotronix, Neuroptix, Genomind, Clearview, Cognicity, Nutricia, Living Media, Verily, RBC, Brain Canada, and CEOs Against Alzheimers. PMD owns shares in Muses Labs, Anthrotronix, Evidation Health, Turtle Shell Technologies and Advera Health Analytics whose products are not discussed here. He has received travel support from World Economic Forum, CCABH and Canaan Ventures. PMD served/serves on the board of Baycrest, AHEL, TLLF and TGHF. PMD is a co-inventor (through Duke) on patents relating to dementia biomarkers and therapies. BD is affiliated with the Institute of Memory and Alzheimer’s Disease (IM2A), Department of Neurology, Salpêtrière Hospital, AP-HP, Sorbonne-Université, Paris, France. JI is affiliated as an Assistant Professor-Adjunct (Group1) with the Department of Family Practice at Queen’s University. She was also a panelist for Hoffman-La Roche Limited, Ottawa, on an Alzheimer’s Disease Panel. She is involved with the Canadian Consortium on Neurodegeneration in Aging (CCNA), Extension Study as a Co- Investigator and Research Coordinator. AI received lecture fees from Eisai, Janssen, Otsuka, Eli Lilly, MSD, Chugai-Roche, Daiichi-Sankyo, Alnylam, Takeda, UCB, Ono, Integra Japan, IQVIA, Fuji Rebio, Biogen, and advisory fees from Janssen during the past three years. AP reports personal fees from Acadia Pharmaceuticals, Functional Neuromodulation, Neurim Pharmaceuticals, Grifols, Eisai, BioXcel, Tetra Discovery Partners, and Merck; grants from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Janssen, Genentech/Roche, Novartis, Merck, as well as funding from NIA, NIMH, DOD. KLP receives grant funding from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Global Brain Health Institute, and Quest Diagnostics. BV has consultancy and research grants from Roche, Biogen, EISAI, Nestle, Lilly, Cerecin, and Merck. HH is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s and Dementia; during the past three years he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. He is co-inventor in the following patents as a scientific expert and has received no royalties: In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784; • Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300; In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463; In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822; In Vitro Method for the Diagnosis of Neurodegenerative Diseases Patent Number: 7547553; CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921. AV is an employee of Eisai Inc. and received lecture honoraria from Roche, MagQu LLC, and Servier.

Disease-modifying pharmacotherapies for Alzheimer's Disease (AD) are currently in late-stage clinical development; once approved, new healthcare infrastructures and services, including primary healthcare, will be necessary to accommodate a huge demand for early and large-scale detection of AD. The increasing global accessibility of digital consumer electronics has opened up new prospects for early diagnosis and management of mild cognitive impairment (MCI) with particular regard to AD. This new wave of innovation has spurred research in both academia and industry, aimed at developing and validating a new "digital generation" of tools for the assessment of the cognitive performance. In light of this paradigm shift, an international working group (the Global Advisory Group on Future MCI Care Pathways) convened to elaborate on how digital tools may be optimally integrated in screening-diagnostic pathways of AD The working group developed consensus perspectives on new algorithms for large-scale screening, detection, and diagnosis of individuals with MCI within primary medical care delivery. In addition, the expert panel addressed operational aspects concerning the implementation of unsupervised at-home testing of cognitive performance. The ultimate intent of the working group's consensus perspectives is to provide guidance to developers of cognitive tests and tools to facilitate the transition toward globally accessible cognitive screening aimed at the early detection, diagnosis, and management of MCI due to AD., Competing Interests: MB is affiliated with the Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain; and with the Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain. Private research funding sources include Grifols SA; Caixabank S.A.; Life Molecular Imaging; Araclon Biotech; Laboratorios Echevarne; Festival Castell Paralada; Bonpreu/Esclat; and Famila Carbó. Public grants include those from Instituto de Salud Carlos III. Ministerio de Salud. Gobierno de España; Dirección General de Farmacia. Ministerio de Salud. Gobierno de España; and European Commission:H2020 program, Innovative Medicine Initiative (IMI-2); and ERA-NET NEURON program, European Marie Sklodowska Curie. Advisory work includes that for Araclon Biotech, Biogen, Bioibérica, Eisai, Grifols, Lilly, Merck, Nutricia, Roche, Oryzon, Schwabe Farma, Servier, and Kyowa Kirin. PMD has received research grants (through Duke University) from Avid, Lilly, Neuronetrix, Avanir, Bauch, Alzheimer’s Drug Discovery Foundation, Cure Alzheimer’s Fund, Wrenn Trust, DOD, ONR, and NIH. PMD has received speaking or advisory fees from Anthrotronix, Neuroptix, Genomind, Clearview, Cognicity, Nutricia, Living Media, Verily, RBC, Brain Canada, and CEOs Against Alzheimers. PMD owns shares in Muses Labs, Anthrotronix, Evidation Health, Turtle Shell Technologies and Advera Health Analytics whose products are not discussed here. He has received travel support from World Economic Forum, CCABH and Canaan Ventures. PMD served/serves on the board of Baycrest, AHEL, TLLF and TGHF. PMD is a co-inventor (through Duke) on patents relating to dementia biomarkers and therapies. BD is affiliated with the Institute of Memory and Alzheimer’s Disease (IM2A), Department of Neurology, Salpêtrière Hospital, AP-HP, Sorbonne-Université, Paris, France. JI is affiliated as an Assistant Professor-Adjunct (Group1) with the Department of Family Practice at Queen’s University. She was also a panelist for Hoffman-La Roche Limited, Ottawa, on an Alzheimer’s Disease Panel. She is involved with the Canadian Consortium on Neurodegeneration in Aging (CCNA), Extension Study as a Co- Investigator and Research Coordinator. AI received lecture fees from Eisai, Janssen, Otsuka, Eli Lilly, MSD, Chugai-Roche, Daiichi-Sankyo, Alnylam, Takeda, UCB, Ono, Integra Japan, IQVIA, Fuji Rebio, Biogen, and advisory fees from Janssen during the past three years. AP reports personal fees from Acadia Pharmaceuticals, Functional Neuromodulation, Neurim Pharmaceuticals, Grifols, Eisai, BioXcel, Tetra Discovery Partners, and Merck; grants from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Janssen, Genentech/Roche, Novartis, Merck, as well as funding from NIA, NIMH, DOD. KLP receives grant funding from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Global Brain Health Institute, and Quest Diagnostics. BV has consultancy and research grants from Roche, Biogen, EISAI, Nestle, Lilly, Cerecin, and Merck. HH is an employee of Eisai Inc. and serves as Senior Associate Editor for the Journal Alzheimer’s and Dementia; during the past three years he had received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. He is co-inventor in the following patents as a scientific expert and has received no royalties: In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300; In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463; In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553; CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797; In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966; Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921. AV is an employee of Eisai Inc. and received lecture honoraria from Roche, MagQu LLC, and Servier.

Introduction: Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD., Methods: S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC)., Discussion: S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846)., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD)-associated neurodegeneration. However, NPS lack a consistent relationship with AD pathology. It is unknown whether any common neural circuits can link these clinically disparate while mechanistically similar features with AD pathology. Here, we explored the neural circuits of NPS in AD-associated neurodegeneration using multivariate pattern analysis (MVPA) of resting-state functional MRI data. Data from 98 subjects (70 amnestic mild cognitive impairment and 28 AD subjects) were obtained. The top 10 regions differentiating symptom presence across NPS were identified, which were mostly the fronto-limbic regions (medial prefrontal cortex, caudate, etc.). These 10 regions' functional connectivity classified symptomatic subjects across individual NPS at 69.46-81.27%, and predicted multiple NPS (indexed by Neuropsychiatric Symptom Questionnaire-Inventory) and AD pathology (indexed by baseline and change of beta-amyloid/pTau ratio) all above 70%. Our findings suggest a fronto-limbic dominated neural circuit that links multiple NPS and AD pathology. With further examination of the structural and pathological changes within the circuit, the circuit may shed light on linking behavioral disturbances with AD-associated neurodegeneration.

Background: Developing non-pharmacological interventions with strong potential to prevent or delay the onset of Alzheimer's disease (AD) in high-risk populations is critical. Aerobic exercise and cognitive training are two promising interventions. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective brain function intensively. Hence, combined aerobic exercise and cognitive training may have a synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested the effects of such a combined intervention, and the findings have been discrepant, largely due to varying doses and formats of the interventions., Methods/design: The purpose of this single-blinded, 2 × 2 factorial phase II randomized controlled trial is to test the efficacy and synergistic effects of a 6-month combined cycling and speed of processing training intervention on cognition and relevant mechanisms (aerobic fitness, cortical thickness, and functional connectivity in the default mode network) in older adults with amnestic mild cognitive impairment. This trial will randomize 128 participants equally to four arms: cycling and speed of processing, cycling only, speed of processing only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline and at 3, 6, 12, and 18 months; cortical thickness and functional connectivity at baseline and at 6, 12, and 18 months; Alzheimer's disease (AD) conversion at 6, 12, and 18 months. The specific aims are to (1) determine the efficacy and synergistic effects of the combined intervention on cognition over 6 months, (2) examine the underlying mechanisms of the combined intervention, and (3) calculate the long-term effect sizes of the combined intervention on cognition and AD conversion. The analysis will use intention-to-treat and linear mixed-effects modeling., Discussion: This trial will be among the first to test the synergistic effects on cognition and mechanisms (relevant to Alzheimer's-associated neurodegeneration) of a uniquely conceptualized and rigorously designed aerobic exercise and cognitive training intervention in older adults with mild cognitive impairment. It will advance Alzheimer's prevention research by providing precise effect-size estimates of the combined intervention., Trial Registration: ClinicalTrials.gov, NCT03313895 . Registered on 18 October 2017.

Objectives: To determine dementia prevalence and costs attributable to dementia using Veterans Health Administration (VHA) data with and without Medicare data., Data Sources: VHA inpatient, outpatient, purchased care and other data and Medicare enrollment, claims, and assessments in fiscal year (FY) 2013., Study Design: Analyses were conducted with VHA data alone and with combined VHA and Medicare data. Dementia was identified from a VHA sanctioned list of ICD-9 diagnoses. Attributable cost of dementia was estimated using recycled predictions., Data Collection: Veterans age 65 and older who used VHA and were enrolled in Traditional Medicare in FY 2013 (1.9 million)., Principal Findings: VHA records indicated the prevalence of dementia in FY 2013 was 4.8 percent while combined VHA and Medicare data indicated the prevalence was 7.4 percent. Attributable cost of dementia to VHA was, on average, $10,950 per veteran per year (pvpy) using VHA alone and $6,662 pvpy using combined VHA and Medicare data. Combined VHA and Medicare attributable cost of dementia was $11,285 pvpy. Utilization attributed to dementia using VHA data alone was lower for long-term institutionalization and higher for supportive care services than indicated in combined VHA and Medicare data., Conclusions: Better planning for clinical and cost-efficient care requires VHA and Medicare to share data for veterans with dementia and likely more generally., (© Health Research and Educational Trust.)

The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale-Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate.

Introduction: Developing biomarkers that distinguish individuals with Alzheimer's disease (AD) from those with normal cognition remains a crucial goal for improving the health of older adults. We investigated adding brain spatial information to temporal event-related potentials (ERPs) to increase AD identification accuracy over temporal ERPs alone., Methods: With two-step principal components analysis, we applied multivariate analyses that incorporated temporal and spatial ERP information from a cognitive task. Discriminant analysis used temporospatial ERP scores to classify participants as belonging to either the AD or healthy control group., Results: Temporospatial ERPs produced a cross-validated area under the curve of 0.84. Adding spatial information through a formal procedure significantly improves classification accuracy., Discussion: A weighted combination of temporospatial ERP markers performs well in detecting AD. Because ERPs are noninvasive and inexpensive, they may be promising biomarkers for AD that can add functional information to other biomarker systems while providing the individual's probability of correct classification.

Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized., Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab., Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies., Results: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups., Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren't effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn't necessarily outweigh associated risks. Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation. Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.

Apolipoprotein E (APOE) ɛ4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimer's disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEɛ4 status (carrier versus noncarrier) and clinical status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEɛ4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEɛ4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.

Aims: The aim was to determine the relationship between (R) and (S)-citalopram enantiomer exposure (AUC(0,24 h)) and therapeutic response in agitated individuals greater than 60 years old with Alzheimer's dementia (AD)., Methods: Citalopram enantiomer exposures (AUC(0,24 h)) derived from an established population pharmacokinetic analysis were utilized to explore the relationship between (R)- and (S)-citalopram area under the curve (AUC(0,24 )) and Mini-Mental State Examination (MMSE), Neurobehavioural Rating Scale-Agitation Subscale (NBRS-A), modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Neuropsychiatric Inventory Agitation subscale (NPIA) scores. Time dependent changes in these scores (disease progression) were accounted for prior to exploring the exposure effect relationship for each enantiomer. These relationships were evaluated using a non-linear-mixed effects modelling approach as implemented in nonmem v7.3., Results: (S)-AUC(0,24 h) and (R)-AUC(0,24 h) each contributed to improvement in NBRS-A scores (k3(R) -0.502; k4(S) -0.712) as did time in treatment. However, increasing (R)-AUC(0,24 h) decreased the probability of patient response (maximum Δ -0.182%/AUC(0,24 h)) based on the CGIC while (S)-AUC(0,24 h) improved the probability of response (maximum Δ 0.112%/AUC(0,24 h)). (R)-AUC(0,24 h) was also associated with worsening in MMSE scores (-0.5 points)., Conclusions: Our results suggest that citalopram enantiomers contributed differentially to treatment outcomes. (R)-citalopram accounted for a greater proportion of the adverse consequences associated with racemic citalopram treatment in patients with AD including a decreased probability of treatment response as measured by the CGIC and a reduction in MMSE scores. The S-enantiomer was associated with increased probability of response based on the CGIC., (© 2016 The British Pharmacological Society.)

Background: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD)., Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS)., Methods: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline., Results: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased., Conclusion: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD.

Background: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory., Methods: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects., Results: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62)., Conclusions: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure., (Published by Elsevier Ltd.)

Objectives: To examine the cognitive and neural effects of vision-based speed-of-processing (VSOP) training in older adults with amnestic mild cognitive impairment (aMCI) and contrast those effects with an active control (mental leisure activities (MLA))., Design: Randomized single-blind controlled pilot trial., Setting: Academic medical center., Participants: Individuals with aMCI (N = 21)., Intervention: Six-week computerized VSOP training., Measurements: Multiple cognitive processing measures, instrumental activities of daily living (IADLs), and two resting state neural networks regulating cognitive processing: central executive network (CEN) and default mode network (DMN)., Results: VSOP training led to significantly greater improvements in trained (processing speed and attention: F1,19  = 6.61, partial η(2)  = 0.26, P = .02) and untrained (working memory: F1,19  = 7.33, partial η(2)  = 0.28, P = .01; IADLs: F1,19  = 5.16, partial η(2)  = 0.21, P = .03) cognitive domains than MLA and protective maintenance in DMN (F1, 9  = 14.63, partial η(2)  = 0.62, P = .004). VSOP training, but not MLA, resulted in a significant improvement in CEN connectivity (Z = -2.37, P = .02)., Conclusion: Target and transfer effects of VSOP training were identified, and links between VSOP training and two neural networks associated with aMCI were found. These findings highlight the potential of VSOP training to slow cognitive decline in individuals with aMCI. Further delineation of mechanisms underlying VSOP-induced plasticity is necessary to understand in which populations and under what conditions such training may be most effective., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Objective: To determine how aging and dementia affect the brain's initial storing of task-relevant and irrelevant information in short-term memory., Methods: We used brain Event-Related Potentials (ERPs) to measure short-term memory storage (ERP component C250) in 36 Young Adults, 36 Normal Elderly, and 36 early-stage AD subjects. Participants performed the Number-Letter task, a cognitive paradigm requiring memory storage of a first relevant stimulus to compare it with a second stimulus., Results: In Young Adults, C250 was more positive for the first task-relevant stimulus compared to all other stimuli. C250 in Normal Elderly and AD subjects was roughly the same to relevant and irrelevant stimuli in Intratrial Parts 1-3 but not 4. The AD group had lower C250 to relevant stimuli in part 1., Conclusions: Both normal aging and dementia cause less differentiation of relevant from irrelevant information in initial storage. There was a large aging effect involving differences in the pattern of C250 responses of the Young Adult versus the Normal Elderly/AD groups. Also, a potential dementia effect was obtained., Significance: C250 is a candidate tool for measuring short-term memory performance on a biological level, as well as a potential marker for memory changes due to normal aging and dementia., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed., Method: In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each., Results: Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam., Conclusions: Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.

Objective: Citalopram has been shown to improve agitation in patients with Alzheimer's disease. The authors evaluated whether other neuropsychiatric symptoms improve with citalopram treatment compared with placebo., Method: In this planned secondary analysis of the Citalopram for Agitation in Alzheimer's Disease study, the authors evaluated the effect of citalopram on the 12 neuropsychiatric symptom domains assessed by the Neuropsychiatric Inventory (NPI). They compared caregiver-reported NPI scores at week 9 in patients receiving citalopram (30 mg/day) or placebo with regard to both the presence or absence of individual neuropsychiatric symptoms and individual domain scores (reflecting severity) in participants who had symptoms at week 9., Results: At week 9, participants treated with citalopram were significantly less likely to be reported as showing delusions (odds ratio=0.40), anxiety (odds ratio=0.43), and irritability/lability (odds ratio=0.38). A comparison of median scores of participants with symptoms present at week 9 showed significant differences favoring citalopram for hallucinations and favoring placebo for sleep/nighttime behavior disorders., Conclusions: While dosage constraints must be considered because of citalopram's adverse effect profile, this agent's overall therapeutic effects in patients with Alzheimer's disease and agitation, in addition to efficacy for agitation/aggression, included reductions in the frequency of irritability, anxiety, and delusions; among patients who had these symptoms at week 9, they included a reduction in the severity of hallucinations but an increase in the severity of sleep/nighttime behavior disorders.

Objective: To assess potential genetic influences on citalopram treatment efficacy for agitation in individuals with Alzheimer dementia (AD). Six functional genetic variants were studied in the following genes: serotonin receptor 2A (HTR2A-T102C), serotonin receptor 2C (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotropic factor (BDNF-Val66Met), apolipoprotein E (ε2, ε3, ε4 variants), and cytochrome P450 (CYP2C19). Treatment response by genotype was measured by (1) the agitation domain of the Neurobehavioral Rating Scale, (2) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change scale (mADCS-CGIC), (3) the agitation domain of the Neuropsychiatric Inventory (NPI), and (4) the Cohen-Mansfield Agitation Inventory., Method: We utilized data from the Citalopram for Agitation in Alzheimer's Disease (CitAD) database. CitAD was a 9-week randomized, double-blind, placebo-controlled multicenter clinical trial showing significant improvement in agitation and caregiver distress in patients treated with citalopram. Proportional odds logistic regression and mixed effects models were used to examine the above-mentioned outcome measures., Results: Significant interactions were noted on the NPI agitation domain for HTR2A (likelihood ratio [LR] = 6.19, df = 2, P = .04) and the mADCS-CGIC for HTR2C (LR = 4.33, df = 2, P = .02) over 9 weeks., Discussion: Treatment outcomes in CitAD showed modest, although statistically significant, influence of genetic variation at HTR2A and HTR2C loci. Future studies should continue to examine the interaction of known genetic variants with antidepressant treatment in patients with AD having agitation., Competing Interests: Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article, (© The Author(s) 2015.)