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Introduction: The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression., Methods: The GENCOMS method relies on robust natural history data and/or placebo arm data from DMT trials. Validated scales that are core to the disease process have been identified, and item level data obtained to standardize the response outcomes from 0 (best possible score) to 1 (worst possible score). A partial least squares regression analysis was conducted with temporal change as the dependent variable and change scores in standardized items as the explanatory variables. The derived model coefficients constitute a weighted sum of items that most effectively measure disease progression., Results: The resultant composite scale was optimized to detect disease progression and can be examined in a range of slow or fast progressing populations. The scale can be used in studies with comparable patient populations as an endpoint optimized to measure disease progression and therefore ideally suited to assess treatment effects in DMTs., Conclusion: The methodology presented here provides a generalizable framework for developing composite scales in the assessment of neurodegenerative disease progression and evaluation of DMT effects. By objectively selecting and weighting items from previously validated measures based solely on their sensitivity to disease progression, this methodology allows for the creation of a more responsive measurement of clinical decline. This heightened sensitivity to clinical decline can be utilized to detect modest yet meaningful treatment effects in the early stages of neurogenerative diseases, when it is optimal to begin a DMT., (© 2024. The Author(s).)

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer's disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address., Competing Interests: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. DA is an investigator in clinical trials sponsored by Alector, Alzheon, Biogen, Eisai, Genentech, Green Valley, Hoffmann-La Roche, Janssen, Medesis Pharma, Novo Nordisk, Otsuka, Regenlife, Toulouse University Hospital, and UCB Pharma. No direct personal benefit is to be declared. JC has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Mangrove Therapeutics, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, ONO, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. JC is supported by NIGMS grant P20GM109025; NIA grant R01AG053798; NIA grant R35AG71476; NIA R25 AG083721-01; Alzheimer’s Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; Joy Chambers-Grundy Endowment. JC is a member of the editorial board of the Journal of Prevention of Alzheimer’s Disease. CL is a full-time employee and shareholder of F. Hoffmann-La Roche Ltd. LM reports research funding from NIHR, UKRI, Johnson and Johnson, Merck, Takeda, Eisai, Gates Ventures and the Davos Alzheimer’s Collaborative (DAC); all to Institution. CS is an employee of CHDI Management, Inc. advisors for CHDI Foundation. and has received consultancy honorarium from Pfizer, Kyowa Kirin, vTv Therapeutics, GW pharmaceuticals, Neuraly, Neuroderm, Neuroxpharm, Inflictis, Biocodex, Thelonious Mind, Novartis, Biogen Green Valley Pharmaceuticals, and Pinteeon Pharmaceuticals. SG received consulting fees from Alzheon, AmyriAD, Eisai Canada, Enigma USA, Lily Canada, Otsuka Canada, Novo Nordisk Canada, TauRx, Advantage, Lundbeck Canada, and royalties from the University of Calgary. SG is a board member of the Sharon Francis Foundation (Toronto). SG is editor-in-chief of JPAD. SC reveived research grants from AbbVie, AgeneBio, Alector, Alnylam, Alzheon, Anavex, Biogen, Cassava Sciences, Eisai, Eli Lilly, GAP, GSK, Green Valley, INmune Bio, Janssen, Novo Nordisk, RetiSpec, Roche, UCB Biopharma, Vielight; all grants were paid to institution only. SC received consulting fees from Alnylam, Alzheimer Society Toronto, Biogen, Biohaven, Bristol-Myers Squibb, Cassava Sciences, Cognivue, Cogstate, Conference Board of Canada, Coverage Policy Task Force (CFPT) Alliance for Aging Research, Eisai, Eli Lilly, INmune Bio, Lundbeck, Novartis, Novo Nordisk, Ontario Dementia Care Alliance (ODCA), Parexel, ProMIS Neuroscience, RetiSpec, Roche, SciNeuro Pharmaceuticals, Voices of Alzheimer’s (VoA); all consulting fees were paid to institution only. RCP has received consulting fees from Roche, Genentech, Eli Lilly, Eisai and Nestle. DMR has nothing to disclose. AMW is a fulltime employee and minor shareholder of Eli Lilly and Company. SBH is owner and employee of Pentara, a company that provides consulting services for dozens of companies in the Alzheimer’s disease space. FJ received fees for advice and lectures (2021-2024) from AC immune, Biogen, Cogthera, Eisai, Eli Lilly, Grifols, Janssen, Novo Nordisk and Roche. MCC is a full-time employee of the Alzheimer’s Association. RSD has nothing to disclose. MI is an employee of Eisai, Inc. JSA is an employee and minor shareholder of Takeda Pharmaceuticals. BV is part of the IHU HealthAge (Research National Agency, France 2030) Toulouse University Hospital and an investigator in clinical trials sponsored by several industry partner. He is part of the JPAD editorial board. He has served in the past 3 years as SAB member for Biogen, Alzheon, Novo Nordisk, Lilly, Eisai France, but received no personal compensation. He has served as consultant for Roche, TauX, EISAI International, Cerecin, Norvo Nordisk (2024) with personal compensation. PSA has received grants from the National Institutes of Health (NIH), the Alzheimer’s Association, Eisai, Lilly; and consulting fees from Roche, Genentech, BMS, Merck, Biogen and Abbvie.

Assessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer's disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach., Competing Interests: S. Dickson, A. Brownlee, B. Haaland, C. Mallinckrodt, and S. Hendrix are employees of Pentara Corporation, a company which consults for Danone Nutricia Research. A.M.J. van Hees is an employee of Danone Nutricia Research. Funding was partly provided by Danone Nutricia Research. T. Hartmann is the LipiDiDiet Coordinator.

Background: Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease., Methods: A 78-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2a study was conducted in Taiwan. Participants were randomised in a 1:1:1 ratio to receive seven intramuscular injections of UB-311 (Q3M arm), or five doses of U311 with two doses of placebo (Q6M arm), or seven doses of placebo (placebo arm). The primary endpoints were safety, tolerability, and immunogenicity of UB-311. Safety was assessed in all participants who received at least one dose of investigational product. This study was registered at ClinicalTrials.gov (NCT02551809)., Findings: Between 7 December 2015 and 28 August 2018, 43 participants were randomised. UB-311 was safe, well-tolerated, and generated a robust immune response. The three treatment-emergent adverse events (TEAEs) with the highest incidence were injection-site pain (14 TEAEs in seven [16%] participants), amyloid-related imaging abnormality with microhaemorrhages and haemosiderin deposits (12 TEAEs in six [14%] participants), and diarrhoea (five TEAEs in five [12%] participants). A 97% antibody response rate was observed and maintained at 93% by the end of the study across both UB-311 arms., Interpretation: These results support the continued development of UB-311., Funding: Vaxxinity, Inc. (Formerly United Neuroscience Ltd.)., Competing Interests: Declaration of interests HJY, J-CD, and AV hold stocks in Vaxxinity, Inc. C-CC has received grant funding from Chang Gung Memorial Hospital CMRPG8J0523, CMRPG8K1532, and CMRPG8J0843. JC has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Biohaven, Cassava, Cerecin, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, GAP Innovations, Grifols, Janssen, Karuna, Eli Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience Ltd., and Unlearn AI pharmaceutical, assessment, and investment companies; JC has received honoraria from Novo Nordisk for chairing a symposium at the Alzheimer's Association International Conference. JC has stock options in Vaxxinity, Inc., Behren Therapeutics, Alzheon, MedAvante-Prophase, and Acumen. JC is the owner of Neuropsychiatric Inventory and receives royalties; JC is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; NIA grant P30AG072959; NIA grant R35AG71476; Alzheimer's Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; and the Joy Chambers–Grundy Endowment. HJY and J-CD are employees of Vaxxinity, Inc. AV is a former employee of United Neuroscience Ltd. SPD is an employee of Pentara Corporation. HL is a former employee of United Neuroscience Ltd. and a current employee of United Biomedical, Inc., Asia. SBH is the owner and an employee of Pentara Corporation, a company contracted to perform statistical analyses of the data for this study. P-NW, M-JC, and C-CH do not have any interests to disclose. C-YW is founder and a major shareholder of the United Biomedical group of companies, including United Biomedical, Inc. Asia, and a founder of United Neuroscience Ltd., which was the sponsor of the clinical trial., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Key points of disagreement between the aducanumab FDA statistical review, which had primarily negative conclusions, and the clinical review, which had primarily positive conclusions, were investigated. Results from secondary endpoints in positive Study 302 were significant and these endpoints provided meaningful additional information. Findings indicate the statistical review of the aducanumab data was incorrect in a number of key areas. Greater placebo decline was not responsible for the significant results in Study 302. Correlations did exist between reduction in β-amyloid and clinical outcomes. Missing data and functional unblinding did not likely bias results. In contrast, the clinical review went too far in saying the negative results in Study 301 did not detract from the positive results in Study 302, as all clinical data should be considered in the evaluation, and the clinical review accepted the company's explanation for divergence of the results between the studies although much of the divergence remained unexplained. Interestingly, both the statistical review and the clinical review considered the available efficacy evidence despite both studies being terminated early. Implications of these findings include that the divergence in results seen in the two phase 3 aducanumab studies can be expected in other studies with similar design and analysis. Therefore, further research is needed to determine if analysis methods other than MMRM and/or optimized outcomes will provide more consistent results across studies., (© 2023. The Author(s).)

Purpose of Review: To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study., Recent Findings: The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months ( p = 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months., Summary: The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD., Competing Interests: SBH is founder, owner and an employee of Pentara Corporation, and consults with dozens of companies in the Alzheimer’s space. She has received consulting fees through Pentara from Nutricia related to this work. HS reports grants from Kuopio University Hospital, Finland (EVO/VTR grant), and Academy of Finland grant 287490, during the conduct of the study, and personal fees from the Steering committee of the Evoke study conducted by Novo Nordisk, outside the submitted work. HS is the Lead medical PI of LipiDiDiet. AS reports a grant from the Academy of Finland (grant 287490), during the conduct of the study. PJV reports grants from the European Commission under the 7th framework program of the European Union (grant agreement number 211696), during the conduct of the study. AMJH and DSC are employees of Danone Nutricia Research. JNJ is a full time employee of Pentara Corporation, a company that consults with dozens of companies in the Alzheimer’s space, including Nutricia. SPD is a full time employee of Pentara Corporation, a company that consults with dozens of companies in the Alzheimer’s space, including Nutricia. KB served as a consultant at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for Biogen, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. MK reports grants from the EU Joint Program BMBF 01ED1509 MIND-AD and the EU Joint Program BMBF 01ED2003 EU-FINGERS, during the conduct of the study; advisory boards for Combinostics, Biogen, and BioArtic; speaker for Biogen, Roche, Nestle, and Nutricia, and reports other grant support from CIMED, Stiftelse Stockholms Sjukhem, ALF. TH reports grants from the European Commission grant agreement number 211696, EU Joint Program BMBF 01ED1509 (MIND-AD), EU Joint Program BMBF 01ED2003 (EU-FINGERS), and Danone Nutricia Research to LipiDiDiet Consortium (month 25-96), during the conduct of the study. TH is the coördinator of LipiDiDiet.

Introduction: Recent clinical trials are considering inclusion of more than just apolipoprotein E ( APOE ) ε4 genotype as a way of reducing variability in analysis of outcomes., Methods: Case-control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)-associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross-validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex-adjusted GenoRisk., Results: The elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747., Discussion: GenoRisk could improve the risk assessment of individuals identified for prevention studies., Competing Interests: Suzanne Hendrix, as the owner of Pentara, received support from Affirmative Diagnostics for the manuscript and received contract work from AC Immmune, Acumen, ADCS, ADDF, Affirmativ Dignpostics, Alector, Alkahest, Allergan, Alzheon, Amylyx, Apodemus, Athira, Avanir, Banner, Biogen, Biohaven, Cadent, Capricor, Cerecin, Cognito, Cognoptix, Cortexyme, Elusis, Green Valley, Grifols, Ionis, Janssen, Kyowa‐Kirin, Lexeo, LuMind, Lundbeck, NCRI, Nilvad, NovoNordisk, Nutricia, Photopharmics, PTCBio, Regenera, Retrotope, Richard Isaacson, Samus, Soleno, Spaulding, Suven, Takeda, Telocyte, Tetra Discovery, Toyama, United Neuroscience, Vaccinex, Vacinity, vTv Therapeutics, and WGU. Suzanne Hendrix has also received royalties from Wiley in the last 36 months; received honoraria for lectures, presentations, etc. from Biogen; received support in the last 36 months from Grifols and Nutricia for presentations and conference attendance; claims one patent pending Brown BL, Hedges DW, Hendrix SB (2014) Extracting A periodic Components from a Time Series Wave Data Set—Patent Pending with a filing date of October 16, 2013, Application Number PCT/US2013/065327; and participated in Alzheon, Cortexyme, and Janssen DSMB or Advisory Board in the last 36 months. Samuel P. Dickson received support from Pentara, which in turn received support from Affirmativ Diagnostics for the manuscript. S. B. Booth received support from Affirmative Diagnostics for the manuscript; received travel support from her employer for work events; ADX provides profit sharing incentives with additional salary which were broadly applied to any work performed for the company (including manuscript generation). J. S. K. Kauwe received support for the manuscript from Brigham Young university and has received honoraria from UH Hilo. B. L. Brown received support through the following grants: Measuring the Interactive Effects of COVID‐19 and Latent Infections on Patterns of cognitive Timing: A Middle‐Aged to Elderly Sample from the Utah Valley Community. Translational Medicine Award from the BYU Simmons Research Endowment ($31,300). This is an intramural grant from a research endowment within our university to my departmental research fund. Brown also claims one patent pending Brown BL, Hedges DW, Hendrix SB (2014) Extracting A periodic Components from a Time Series Wave Data Set—Patent Pending with a filing date of October 16, 2013, Application Number PCT/US2013/065327. Data used in this manuscript is publically available. Participant consent is not needed, and was obtained from investigators who ran each study. M. L. Hardy has received paid consulting fees to the LLC solely owned by ML Hardy from ixLayer, NW Pathology & Labs, Mt. Baker Imaging, PlumCare, ADx Healthcare, Architectural Elements; received travel support from her employer for work events; and was the past Volunteer Secretary for the Lets Pool Together and Hope Philantropies non‐profit boards. P. G. Ridge had received honoraria from University of Kansas Alzheimer's Disease Center for a seminar presentation. R. R. Fortna is a board member of Northwest Pathology and ADx Healthcare and is co‐owner and holds stock for ADx healthcare. J. Nicodemus Johnson has nothing to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any data gaps to be filled and plans any additional research required to support the qualification. Accumulating, interpreting and analyzing available data is outlined, step-by-step, illustrated by a qualified enrichment biomarker example and a safety biomarker in the process of qualification. The detailed steps aid requestors seeking qualification of biomarkers, allowing them to organize the available evidence and identify potential gaps. This provides a statistical perspective for assessing evidence that parallels clinical considerations and is intended to guide the overall evaluation of evidentiary criteria to support a specific biomarker COU.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention., Methods: In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5-item composite). Analyses were by modified intention-to-treat, excluding (ie, censoring) data collected after the start of open-label active product and/or AD medication., Results: Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5-item composite (-60%; between-group difference 0.212 [95% confidence interval: 0.044 to 0.380]; P = 0.014), Clinical Dementia Rating-Sum of Boxes (-45%; P = 0.014), memory (-76%; P = 0.008), and brain atrophy measures; small to medium Cohen's d effect size (0.25-0.31) similar to established clinically relevant AD treatment., Discussion: This multinutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long-term use., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5 years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial., Methods: This study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n = 868) compared to those who remained cognitively unimpaired during the same time period (n = 989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer's Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11 years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score., Results: The optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities + 2.24*MMSE Orientation to Time + 2.14*MMSE Orientation to Place + 0.53*Logical Memory Delayed Recall + 1.36* Word List-Delayed Recall + 0.68*Judgment of Line Orientation + 1.39*Raven's Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was - 1.10 over 1 year., Conclusions: The APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11 years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.

As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure., Competing Interests: SBH and NNE report financial compensation for statistical analysis from Danone Nutricia Research. HS reports personal fees from ACImmune and MERCK, outside the submitted work. AMJH and AA are employees of Danone Nutricia Research. PJV reports grants from Inn ovative Medicine Initiative and ZonMw, during the conduct of the study, and non-financial support from GE Healthcare and grants from Biogen, outside the submitted work. AS reports grants from Academy of Finland, during the conduct of the study, and grants from Alzheimerfonden Sweden and Stockholm County Council (ALF), outside the submitted work. MK reports grants from EU Joint Program - Neurodegenerative Disease Research (MIND-AD), during the conduct of the study, and grants from Alzheimerfonden Sweden, Stockholm County Council (ALF), Academy of Finland, Swedish Research Council, Knut and Alice Wallenberg Foundation, Center for Innovative Medicine at Karolinska Institutet, Sweden, and Stiftelsen Stockholms Sjukhem, Sweden, outside the submitted work. TH reports grants from EU FP7 (LipiDiDiet), EU Joint Program - Neurodegenerative Disease Research (MIND-AD), and Danone Nutricia Research (LipiDiDiet Extension), during the conduct of the study. KB has nothing to disclose.

Background: Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial., Methods: LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705., Findings: Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was -0·028 (SD 0·453) in the active group and -0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI -0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of -0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention., Interpretation: The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed., Funding: European Commission 7th Framework Programme., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

Background: Development of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials., Methods: Partial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients' early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations., Results: ADCOMS consists of 4 Alzheimer's Disease Assessment Scale-cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating-Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials., Conclusions: ADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Event-related potentials (ERPs) are a physiological measure of cognitive function that have shown diagnostic and prognostic utility in Alzheimer's disease (AD). In this study, we used a novel eigenvector-based technique to better understand brain electrophysiological differences between subjects with mild AD and healthy controls (HC). Using ERPs from 75 subjects with mild AD and 95 HC, we first calculated cognitive task eigenvectors within each subject from three conditions and then calculated second-order eigenvector components to compare the AD group to the HC group. A MANOVA of the three second-level components discriminated between AD and HC multivariately (Wilks' lambda=.4297, p<0.0001, R2 = .5703), and also on each of the three components univariately (all 3 p-values<0.0001). The eigenvector-based technique used in this study accurately discriminated between the mild AD group and HC. As such, this analysis method adds to our understanding of the differences in ERP signal between AD and HC, and could provide a sensitive biomarker for diagnosis and monitoring of AD progression., Competing Interests: B. Brown, S. Hendrix and D. Hedges have a patent pending related to the analysis methodology applied to the ERP curves. No conflicts are reported by the remaining authors.

Introduction: Treatment in moderate or severe Alzheimer's disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index., Methods: Data were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline ("snapshot analysis"), performed using a mixed-effects model with repeated measures (MMRM)., Results: Over the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: -74.3 versus -28.2, P = 0.003; CIBIC-Plus: -2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: -74.3 versus -7.4, P <0.001; CIBIC-Plus: -2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (-0.9), P = 0.407; versus memantine-only (-12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both., Conclusions: This large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.

Background: There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials., Methods: Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations., Results: The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64., Conclusions: We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention Initiative's preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials., Method: We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains., Results: The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05)., Conclusions: We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Addressing causes of heterogeneity in cognitive outcomes is becoming more critical as Alzheimer's disease (AD) research focuses on earlier disease. One of the causes of this heterogeneity may be that individuals with deficiencies in different cognitive domains may perform similarly on a neuropsychological (NP) test for very different reasons. Tatsuoka and colleagues have applied a Bayesian model in order to integrate knowledge about cognitive domains relevant to each NP test with the observed outcomes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) mild cognitive impairment data. This approach resulted in better prediction of AD diagnosis than more traditional approaches.

Recent biomarker research has improved the identification of individuals with very early stages of Alzheimer's disease (AD) and has demonstrated that biomarkers are sensitive for measuring progression in the pre-dementia or mild cognitive impairment (MCI) stage and even pre-symptomatic or pre-MCI stage of AD. Because there are no validated biomarkers in AD, it is important to seek out clinical outcomes that are also sensitive for measuring progression in these very early stages of disease. Clinical outcomes are more subjective and more affected by measurement error than biomarkers but represent the core aspects of the disease and are critical for validation of biomarkers and for evaluation of clinical relevance. Identification of individuals with pre-MCI stages of AD will need to continue to rely on biomarkers, but the identification of individuals with MCI who will progress to AD can be achieved with biomarkers or clinical criteria. Although standard clinical outcomes have been shown to be less sensitive to progression than biomarker outcomes in MCI and pre-MCI populations, non-standard scoring has improved the performance of the Alzheimer's Disease Assessment Scale cognitive subscale, making it more sensitive to progression. Neuropsychological cognitive testing items are optimal for measuring progression in pre-MCI populations, and current research is exploring the best ways to combine these items into a composite cognitive score with maximum responsiveness. In an MCI stage, cognitive, functional, and global items all change, and the best single composite score for measuring progression may involve all of these aspects of the disease. The best chance of success in demonstrating treatment effects in clinical trials will be achieved in a well-defined pre-MCI or MCI population and with an outcome that tracks well with clinical progression over time and with time. A partial least squares model can be used to identify these optimal weighted combinations.

A recent article by Schneider and colleagues has generated a lot of interest in simulation studies as a way to improve study design. The study also illustrates the foremost principal in simulation studies, which is that the results of a simulation are an embodiment of the assumptions that went into it. This simulation study assumes that the effect size is proportional to the mean to standard deviation ratio of the Alzheimer Disease Assessment Scale - cognitive subscale in the population being studied. Under this assumption, selecting a subgroup for a clinical trial based on biomarkers will not affect the efficiency of the study, despite achieving the desired increase in the mean to standard deviation ratio.

Background: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD., Methods: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316)., Findings: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg tarenflurbil group for months 12-24 (all p<0.05)., Interpretation: 800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD., Funding: Myriad Pharmaceuticals.

The violent and peaceful behaviors of 115 children who had or had not witnessed domestic violence were measured in five types of simulated conflict. Witnesses did not differ from nonwitnesses in conflicts involving limited resources, jealousy over possessions, or intimidation; witnesses were significantly more violent in conflicts involving aggression and exclusion. The most violent responses were found among abusers' sons who had been excluded by peers., (2007 APA, all rights reserved)

Child witnesses' use of violent or peaceful strategies to resolve conflicts with peers were compared with strategies used by nonwitnesses. Stories depicting 5 types of peer conflicts were presented to each child, and the strategies used by the child to reach peaceful resolutions were scored. Findings include differences between witnesses and nonwitnesses, differences between genders, differences according to types of conflicts, and individual differences.