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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.

Competing Interests: Dr C. Sampaio received consultancy honoraria from NeuroDerm, Pinteon Pharmaceuticals, Pharma2B, Biocodex, Inflictis. She is partner at Thelonius Mind, Consultants. And she receives salary from CHDIManagement/CHDI Foundation, Inc.

Objectives: To test the hypothesis that higher level of purpose in life is associated with lower likelihood of dementia and mild cognitive impairment (MCI) in older Brazilians., Methods: As part of the Pathology, Alzheimer's and Related Dementias Study (PARDoS), informants of 1,514 older deceased Brazilians underwent a uniform structured interview. The informant interview included demographic data, the Clinical Dementia Rating scale to diagnose dementia and MCI, the National Institute of Mental Health Diagnostic Interview Schedule for depression, and a 6-item measure of purpose in life, a component of well-being., Results: Purpose scores ranged from 1.5 to 5.0 with higher values indicating higher levels of purpose. On the Clinical Dementia Rating Scale, 940 persons (62.1%) had no cognitive impairment, 121 (8.0%) had MCI, and 453 (29.9%) had dementia. In logistic regression models adjusted for age at death, sex, education, and race, higher purpose was associated with lower likelihood of MCI (odds ratio = .58; 95% confidence interval [CI]: .43, .79) and dementia (odds ratio = .49, 95% CI: .41, .59). Results were comparable after adjusting for depression (identified in 161 [10.6%]). Neither race nor education modified the association of purpose with cognitive diagnoses., Conclusions: Higher purpose in life is associated with lower likelihood of MCI and dementia in older black and white Brazilians.

Combination therapy is expected to play an important role for the treatment of Alzheimer's disease (AD). In October 2018, the European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) met to discuss scientific, regulatory, and logistical challenges to the development of combination therapy for AD and current efforts to address these challenges. Task Force members unanimously agreed that successful treatment of AD will likely require combination therapy approaches that target multiple mechanisms and pathways. They further agreed on the need for global collaboration and sharing of data and resources to accelerate development of such approaches., Competing Interests: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Gauthier reports personal fees from TauRx, Lundbeck Institute, and Esai; and grants from Lilly and Roche, outside the submitted work. Dr. Alam reports personal fees (employment) from EIP Pharma, Inc, outside the submitted work. Dr. Fillit discloses the following consulting relationships during the past 3 years: Axovant, vTv, Lundbeck, Otsuka, Lilly, RTI, Roche, Genentech, Merck, Samus, Pfizer. He reports no conflicts of interest related to these disclosures that are relevant to this publication. Dr. Iwatsubo has nothing to disclose. Dr. Liu-Seifert reports other from Lilly, outside the submitted work. Dr. Sabbagh has consulted for Allergan, Biogen, Bracket, Neurotrope, Cortexyme, Roche, Grifols, Sanofi, VTV therapeutic, and Alzheon. Dr Sslloway has nothing to disclose; Dr. Sims, employee of Eli Lilly and Company and holder of stock in Eli Lilly and Company. Dr. Sperling is an employee of H. Lundbeck A/S, outside the submitted work. Dr. Sperling reports grants from Janssen, during the conduct of the study; personal fees from AC Immune, personal fees from Biogen, personal fees from Roche, personal fees from Eisai, personal fees from Insightec, personal fees from Takeda, personal fees from Merck, personal fees from General Electric, outside the submitted work. Dr. Welsh-Bohmer has contracts with Takeda Pharmaceutical Company and with VeraSci where she is the VP for Neurodegenerative Disorders. Dr. Touchon has nothing to disclose; Dr. Vellas reports grants from Lilly, Merck, Roche, Lundbeck, Biogen, grants from Alzheimer’s Association, European Commission, personal fees from Lilly, Merck, Roche, Biogen, outside the submitted work; Dr. Aisen reports grants from Lilly, personal fees from Proclara, other from Lilly, other from Janssen, other from Eisai, grants from Janssen, grants from NIA, grants from FNIH, grants from Alzheimer’s Association, personal fees from Merck, personal fees from Roche, personal fees from Lundbeck, personal fees from Biogen, personal fees from ImmunoBrain Checkpoint, outside the submitted work.

Although the results were disappointing from two recent clinical trials of amyloid-targeting drugs in mild-to-moderate AD, the trials provided information that will be important for future studies, according to the EU-US CTAD Task Force, which met in November 2017 to discuss the EXPEDITION3 and EPOCH trials. These trials tested two of the predominant drug development strategies for AD: amyloid immunotherapy and BACE inhibition in populations largely composed of mild AD dementia patients. The results of these trials support the emerging consensus that effective amyloid-targeted treatment will require intervention in early, even pre-symptomatic stages of the disease. Further, the Task Force suggested that a refinement of the amyloid hypothesis may be needed and that other hypotheses should be more fully explored. In addition, they called for improved biomarkers and other outcome assessments to detect the earliest changes in the development of AD., Competing Interests: At the time of the Task Force meeting, DM was a full-time employee of Merck, Inc. and ES was a full-time employee of Eli Lilly and Company, and currently holds stock in the company. The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work

Background: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development., Methods: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data., Results: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011., Conclusions: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency., (Copyright © 2014 The Alzheimer's Association. All rights reserved.)

While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease.

Despite enormous financial and scientific efforts, still no approved disease-modifying therapies exist for Alzheimer's disease (AD). During the last decade all Phase III clinical trials on disease modifiers in AD have failed. The dementia stage of AD being probably too late in order to allow for successful disease modification has been identified as a possible culprit that could explain the failure of so many clinical trials. In parallel, a major development in the diagnostic research field of AD was achieved by the recent proposal of new diagnostic criteria for AD, which also specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD, thus extending the traditional definition of disease to very early stages that may be a more feasible target for various disease modifying therapeutic interventions. This ongoing paradigm shift in AD definition and diagnosis represents a fundamental basis for redefinition of interventional trials in AD, allowing to specifically focus on preventative measures during very early pathophysiologically confirmed stages of disease. This consensus paper reflects the outcome from a European Union and North American Task Force meeting comprised of experts from academia, industry, private foundations, and regulatory agencies that was convened in Toulouse, France on November 5, 2010 and that focused on prevention trials in AD. This position paper thoroughly analyzes prerequisites for successful preventative trials in AD and concludes with concrete recommendations on biomarkers, statistical tools and other variables important for improved study designs suitable for preventative as well as for early therapeutic interventional trials in AD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia., Method: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD., Results: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods., Conclusion: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

Biomarkers are key for the different phases of drug development in Alzheimer Disease and in other fields. Traditionally the process of biomarker qualification has been slow, mostly exclusively academic. Regulators were mostly passive spectators. The Pharmaceutical innovation crisis of the end of XX century prompted the regulatory agencies and the governments from both sides of the Atlantic to initiate a number of programs to foster renovation, creativity and new paradigms. This created the opportunity for regulators to move from a passive position to a more active role, as facilitators. However, it is becoming apparent that there is room for even more central roles for regulators in the interactive consortia that are now in place. It is also becoming apparent that regulatory agencies are expected to become highly specialized hubs holding expert "know-how" not easily available elsewhere.

Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimer's disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimer's disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimer's disease, and for trials in severe Alzheimer's disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.

After symptomatic treatments, the new target for therapeutic approaches in Alzheimer's disease is the development of disease-modifying drugs. The concept of disease modification in Alzheimer's disease is controversial and the design of these trials raises many questions. Which populations should be studied? For how long? With which principal and secondary endpoints? Are surrogate markers available? Here, we present a European consensus on disease-modifying trials in Alzheimer's disease, agreed under the auspices of the European Alzheimer's Disease Consortium and based on the European perspective of the concept of disease modification, study designs, the role for biomarkers, risk benefit, and pharmacoeconomic issues.