# The Future of Anti-Amyloid Trials

P.S. Aisen, J. Cummings, R. Doody, Lynn Kramer, S. Salloway, D.J. Selkoe, J. Sims, R.A. Sperling, Bruno Vellas

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P.S. Aisen, J. Cummings, R. Doody, Lynn Kramer, S. Salloway, et al.. The Future of Anti-Amyloid Trials. The Journal of prevention of Alzheimer's disease, 2020, 7 (3), pp.146-151. 10.14283/jpad.2020.24. hal-04477620

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# The Future of Anti-Amyloid Trials

P.S. Aisen¹, J. Cummings², R. Doody³, L. Kramer⁴, S. Salloway⁵, D.J. Selkoe⁶, J. Sims⁷, R.A. Sperling⁶, B. Vellas⁸ and the EU/US CTAD 2019 Task Force*

* EU/US/CTAD TASK FORCE: Susan Abushakra (Framingham); Paul Aisen (San Diego); John Alam (Boston); Sandrine Andrieu (Toulouse); Anu Bansal (Simsbury); Monika Baudler (Basel); Joanne Bell (Wilmington); Mickaël Beraud (Zaventem); Tobias Bittner (Basel); Samantha Budd Haeberlein (Cambridge); Szofia Bullain (Basel); Marc Cantillon (Gilbert); Maria Carrillo (Chicago); Carmen Castrillo-Viguera (Cambridge); Ivan Cheung (Woodcliff Lake); Julia Coelho (San Francisco); Jeffrey Cummings (Las Vegas); Michael Detke (San Francisco); Daniel Di Giusto (Basel); Rachelle Doody (South San Francisco); John Dwyer (Washington); Michael Egan (North Wales); Colin Ewen (Slough); Charles Fisher (San Francisco); Serge Gauthier (Montreal); Michael Gold (North Chicago); Harald Hampel (Woodcliff Lake); Ping He (Cambridge); Suzanne Hendrix (Salt Lake City); David Henley (Titusville); Michael Irizarry (Woodcliff Lake); Atsushi Iwata (Tokyo); Takeshi Iwatsubo (Tokyo); Michael Keeley (South San Francisco); Geoffrey Kerchner (South San Francisco); Gene Kinney (San Francisco); Hartmuth Kolb (Titusville); Marie Kosco-Vilbois (Lausanne); Lynn Kramer (Westport); Ricky Kurzman (Woodcliff Lake); Lars Lannfelt (Uppsala); John Lawson (Malvern); Jinhe Li (Gilbert); Frank Longo (Stanford); Mark Mintun (Philadelphia); Vaidrius Navikas (Valby); Gerald Novak (Titusville); Gunilla Osswald (Stockholm); Susanne Ostrowitzki (South San Francisco); Anton Porsteinsson (Rochester); Rema Raman (San Diego); Ivana Rubino (Cambridge); Marwan Sabbagh (Las Vegas); Stephen Salloway (Providence); Rachel Schindler (New York); Lon Schneider (Los Angeles); Hiroshi Sekiya (Malvern); Dennis Selkoe (Boston); Eric Siemens (Zionsville); John Sims (Indianapolis); Lisa Sipe (San Marcos); Olivier Sol (Lausanne); Reisa Sperling (Boston); Andrew Stephens (Berlin); Johannes Streffer (Braine-l'Alleud); Joyce Suhy (Newark); Chad Swanson (Woodcliff Lake); Gilles Tamagnan (New Haven); Rudolph Tanzi (Boston); Pierre Tariot (Phoenix); Edmond Teng (South San Francisco); Martin Tolar (Framingham); Jacques Touchon (Montpellier); Martin Traber (Basel); Bruno Vellas (Toulouse); Andrea Vergallo (Woodcliff Lake); Christian Von Hehn (Cambridge); George Vradenburg (Washington); Judy Walker (Singapore); Michael Weiner (San Francisco); Glen Wunderlich (Ridgefield); Haichen Yang (North Wales); Wagner Zago (San Francisco); Jennifer Ann Zimmer (Indianapolis); Thomas Zoda (Austin)

1. Alzheimer's Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA; 2. Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, and Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada, USA; 3. Genentech/ Roche, Basel, Switzerland; 4. Eisai Co., Ltd., Eisai, Inc., Woodcliff Lake, NJ, USA; 5. The Warren Alpert Medical School of Brown University, Providence RI, USA; 6. Brigham and Women's Hospital, Boston MA, USA; 7. Eli Lilly and Company, Indianapolis, IN, USA; 8. Gerontopole, INSERM U1027, Alzheimer's Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France

Corresponding Author: P.S. Aisen, University of Southern California Alzheimer's Therapeutic Research Institute, San Diego, CA, USA, paisen@usc.edu

J Prev Alz Dis 2020;3(7):146-151

Published online April 17, 2020, http://dx.doi.org/10.14283/jpad.2020.24

## Abstract

The termination of many clinical trials of amyloid-targeting therapies for the treatment of Alzheimer's disease (AD) has had a major impact on the AD clinical research enterprise. However, positive signals in recent studies have reinvigorated support for the amyloid hypothesis and amyloid-targeting strategies. In December 2019, the EU-US Clinical Trials on Alzheimer's Disease (CTAD) Task Force met to share learnings from these studies in order to inform future trials and promote the development of effective AD treatments. Critical factors that have emerged in studies of anti-amyloid monoclonal antibody therapies include developing a better understanding of the specific amyloid species targeted by different antibodies, advancing our insight into the mechanism by which those antibodies may reduce pathology, implementing more comprehensive repertoires of biomarkers into trials, and identifying appropriate doses. Studies suggest that Amyloid-Related Imaging Abnormalities – effusion type (ARIA-E) are a manageable safety concern and that caution should be exercised before terminating studies based on interim analyses. The Task Force concluded that opportunities for developing effective treatments include developing new biomarkers, intervening in early stages of disease, and use of combination therapies.

Key words: Alzheimer's disease, dementia, amyloid hypothesis, monoclonal antibody treatment, BACE inhibitors, combination therapy.

## Introduction

Despite encouraging results from the aducanumab Phase 1 and BAN2401 Phase 2 anti-amyloid antibody clinical trials, amyloid-beta protein (Aβ)-based strategies for the treatment of Alzheimer's disease (AD) appeared to take a crippling blow in March 2019 when Biogen announced it was terminating two clinical trials (EMERGE and ENGAGE) of the anti-Aβ monoclonal antibody aducanumab based on the results of an interim analysis demonstrating a lack of benefit or 'futility.' The field had another major challenge in July when Novartis, Amgen, and the Banner Alzheimer's Institute announced termination of pivotal trials of the beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor umibecstat after an interim analysis identified cognitive worsening in trial participants. This marked the fifth failed BACE inhibitor in less than two years, two with trials stopped because of adverse events (Merck's verubecstat and Janssen's atabecestat) and two trials stopped for lack of efficacy (Astra Zeneca and Eli Lilly's lanabecstat and Eli Lilly's LY3202626) (1-3). A fifth BACE inhibitor trial of Eisai and Biogen's elenbecstat was halted in September 2019 due to an unfavorable risk/benefit profile (4). Trials for another anti-Aβ monoclonal antibody, Genentech and Roche's crenezumab, were terminated in 2019 for futility (5).

Then, in October, a stunning reversal: Biogen
announced that the futility analysis in the aducanumab trial was misleading. Analysis of a larger data set indicated that aducanumab did indeed slow cognitive decline in trial participants who received a higher dose of the drug for longer periods of time in one of the two studies. Following this announcement, Biogen indicated they planned to submit aducanumab to the U.S. Food and Drug Administration (FDA) for regulatory approval. Any form of approval for aducanumab has the potential to transform the AD field, providing hope for patients and researchers alike. Regulatory success could also reinvigorate support for the amyloid cascade hypothesis, which posits that deposition of Aβ in the brain leads to the neurodegeneration and dementia that characterize AD. This hypothesis has driven the development of AD therapeutics for decades. Secretase inhibitors block production of Aβ, while anti-Aβ antibodies are designed to clear Aβ and prevent the formation of amyloid plaques as well as neutralize soluble Aβ oligomers. Prior to the announcement of aducanumab's potential beneficial effects, no secretase inhibitor and only two monoclonal antibodies --- BAN2401 and gantenerumab --- had preliminary evidence of possible efficacy against Aβ, and there was much speculation in the field that the amyloid hypothesis was dead or at least unhelpful in guiding development of AD therapeutics. However substantial emerging evidence supports the amyloid cascade hypothesis (6).

To better understand the implications of these clinical trial results and the future of amyloid-based therapies, the European Union and United States Clinical Trials on Alzheimer's Disease Task Force (EU/US CTAD-TF) convened a meeting in San Diego on December 4, 2019, bringing together industry scientists involved in clinical trials of anti-Aβ and other AD therapies along with representatives from pharmaceutical, biotechnology, diagnostics, and medical device companies, academic researchers, clinicians, and non-profit organizations. Their goal was to articulate lessons learned from these trials with the hope of enabling future successful trials that will lead to the approval of effective treatments for AD.

## Learnings from trials of anti-amyloid monoclonal antibody trials

The Task Force discussed five anti-amyloid monoclonal antibody therapies currently in clinical development: aducanumab (7), BAN2401 (6), gantenerumab (8), solanezumab (9-13), and donanemab. Other anti-amyloid monoclonal antibodies (e.g., crenezumab) are also in development (5, 14). As summarized in Table 1, these antibodies target different forms of amyloid, may have different mechanisms of action, and are being tested for efficacy at different stages of disease.

## The importance of dose

The futility analysis in the ENGAGE and EMERGE aducanumab trials – two identically designed Phase 3 studies -- was based on a pooled interim dataset of approximately 50% of enrolled participants using a probability calculation that assumed non-heterogeneity between the two studies. A subsequent analysis of a larger dataset, however, revealed that protocol amendments allowing increased dosing in apolipoprotein E epsilon 4 (APOE4) carriers had differential effects on the two studies due to the relative timing of enrollment. This analysis demonstrated a statistically significant reduction in clinical decline across multiple clinical endpoints among early AD patients in EMERGE, likely due to high dose exposure to the drug. Participants in the ENGAGE trial who had received higher doses (10 mg/kg) for at least 10 doses had clinical effects similar to those of the EMERGE participants. Amyloid positron emission tomography (PET) studies demonstrated dose-dependent reduction of brain amyloid deposition across both trials.

Other trials have also demonstrated substantial dose-related amyloid lowering. Study 201 of BAN2401 used an adaptive randomization design with six arms to understand the impact of dose and minimize the number of participants treated with ineffective doses. The highest dose (10 mg/kg biweekly) produced the greatest slowing of disease progression and most robust reduction in brain amyloid levels compared to placebo and is used in the recently-launched Phase 3 Clarity AD study.

Open-label extensions of two early Phase 3 gantenerumab trials, in which study participants were assigned one of five titration schemes, also showed that five times higher dose of gantenerumab than was used in the earlier phase 3 studies drove increased amyloid reduction assessed with amyloid PET imaging (15). These findings prompted the initiation of a new Phase 3 program using this five-fold higher doses.

## Mechanism matters

Amyloid is not a monolithic target but a family of monomers, oligomers, protofibrils, and fibrils; and different anti-Aβ antibodies target partially different species. The molecular dynamics by which targeting different species results in variable effects on plaque burden and brain volume loss are not well understood; however, these differential mechanisms may help explain the different trial effects observed.

Solanezumab was hypothesized to remove brain amyloid through what is called the “peripheral sink hypothesis,” i.e., by increasing the clearance of soluble Aβ via the formation of antibody-Aβ complexes in the plasma. However, pharmacodynamic studies showed that a reduction of Aβ in the peripheral compartment failed to shift the equilibrium between Aβ species enough
<table><caption>Table 1. Anti-amyloid monoclonal antibody therapies</caption><thead><tr><th>Drug Name (Sponsor)</th><th>Amyloid species targeted</th><th>Putative mechanism of action</th><th>Clinical trials</th><th>Target Population</th><th>Results</th><th>Status of development</th><th>References</th></tr></thead><tbody><tr><td>Aducanumab (Biogen)</td><td>Aggregated Aβ</td><td></td><td></td><td>EMERGE and ENGAGE (Phase 3)<br>MCI due to AD and mild AD dementia with positive amyloid PET scan</td><td>Futility analysis showed no significant reduction in cognitive decline<br>Biomarkers: CSF pTau and total Tau reduced<br>Decreased SUVR on amyloid PET</td><td>Terminated March 2019 based on futility analysis<br>Further analysis showed reduced cognitive decline at high dose<br>Plan to submit regulatory filing</td><td>Sevigny 2016</td></tr><tr><td>Gantenerumab, (Roche)</td><td>Aβ fibrils, oligomers, aggregated Aβ</td><td>Reduce plaques by recruiting microglia</td><td></td><td>2/3 of participants ApoE4 carriers<br>SCarlet RoAD (Phase 3)<br>MCI due to AD with CSF evidence of amyloid pathology</td><td>Biomarkers: decreased SUVR on amyloid PET, and decreased CSF tau, phospho-tau, and neurogranin<br>Biomarkers: decreased brain amyloid or amyloid PET scans</td><td>Open-label extension with titration<br>Terminated with SCarlet RoAD<br>Open-label extension with titration to higher dose</td><td>Ostrowitzki 2017</td></tr><tr><td>Crenezumab (Roche)</td><td>Aβ monomers, oligomers</td><td>Removal of Aβ oligomers while minimizing microglial activation and inflammation</td><td></td><td>Marguerite RoAD (Phase 3)<br>Mild dementia due to AD with CSF evidence of amyloid pathology<br>GRADUATE 1 and 2 (Phase 3)<br>MCI due to AD and mild AD dementia with evidence of amyloid pathology by CSF or amyloid PET scan<br>Subcutaneous administration<br>ABBY (Phase 2) in mild-to-moderate AD<br>BLAZE (Phase 2) biomarker study<br>CREAD 1 and 2<br>Prodromal to mild AD<br>API study in Autosomal Dominant AD</td><td>Biomarkers: no effect on hippocampal, ventricular, or whole brain volume; increased CSF Aβ<sub>42</sub></td><td>Ongoing trials with higher doses of drug</td><td></td></tr><tr><td>Solanezumab (Eli Lilly)</td><td>Soluble, monomeric Aβ</td><td>Binds monomeric Aβ to shift equilibrium away from more complex species from dimers to plaque</td><td></td><td>EXPEDITION 1 and 2 (Phase 3) – mild to moderate AD<br>EXPEDITION 3 (Phase 3) – clinical diagnosis of mild dementia due to AD plus evidence of amyloid pathology<br>DIAN-TU Study in Dominantly Inherited AD<br>Anti-Amyloid treatment of Asymptomatic Alzheimer's Disease (A4)</td><td>Stopped early<br>Stopped early<br>Primary endpoint not met.</td><td>Failed to meet primary and secondary endpoints.<br>Stopped for futility on CDR-SB</td><td>Cummings 2018</td></tr><tr><td>BAN 2401 (Eisai)</td><td>Soluble and insoluble Aβ aggregates</td><td>Bind and clear plaques and soluble toxic aggregated Aβ species</td><td></td><td>Study 201 (Phase 2) – MCI due to AD or mild AD. Adaptive randomization<br>Clarity AD (Phase 3) – MCI due to AD or early AD with amyloid pathology<br>AHEAD 3-45 in Preclinical AD with intermediate (A3) and elevated (A45) amyloid<br>TRAILBLAZER (Phase 2) in combination with BACE inhibitor</td><td>Slowing of cognitive decline<br>Biomarkers: multiple ATN biomarkers (pTau, total tau, neurogranin, NFL) moved in expected direction.</td><td>Active study, not recruiting.</td><td>Farlow 2012,<br>Doody 2014,<br>Siemers 2016<br>Horig 2018,<br>Schwarz 2019</td></tr><tr><td>Donanemab (Eli Lilly)</td><td>Pyroglutamate forms of Aβ found in amyloid plaques</td><td>Microglial mediated removal of plaque</td><td></td><td></td><td></td><td>Open-label extension</td><td>van Dyck 2018</td></tr></tbody></table>
to cause a substantial reduction of fibrillary Aβ in the brain (16); the possible beneficial effect of solanezumab on cognitive decline may nonetheless be mediated by its binding to smaller, diffusible forms. Other possible mechanisms of anti-Aβ antibodies include direct targeting of Aβ plaques or other toxic species of Aβ for removal or activating phagocytosis of Aβ by microglia (17). Clinical trials of solanezumab in mild-moderate AD and in prodromal/mild AD failed to show a drug-placebo difference and no effects on biomarkers were observed. Solanezumab continues in the Anti-Amyloid treatment of Asymptomatic Alzheimer's disease (A4) study of cognitively asymptomatic participants with positive amyloid imaging.

The effects of anti-Aβ antibodies on brain volume loss is poorly understood. In the EXPEDITION trials, treatment with solanezumab showed a modest but statistically insignificant slowing of brain atrophy (13). Gantenerumab produced no such effects on the measures collected (8). One theory suggests that driving down amyloid may itself be reflected as a reduction in brain volume. The effects on brain volume, however, could differ depending on which form of amyloid the antibody targets (e.g. plaques versus oligomeric forms). Further analysis of data from anti-Aβ antibody trials may help clarify this issue. The correlation of treatment-related brain volume loss and disease progression is also unclear.

## ARIA appears to be a manageable safety concern

The incidence of amyloid-related imaging abnormalities – effusion type (ARIA-E) associated with anti-Aβ antibody treatment has been a substantial concern in the development of these therapies (18). For example, in the aducanumab trials, ARIA-E was seen in more than one-third of participants, although these episodes were typically asymptomatic and resolved within 4-16 weeks without long-term sequelae. ARIA-E was also observed in about 10% of participants in the BAN2401 Phase 2 study, occurring primarily in the first three months of treatment.

Recent studies suggest that ARIA-E can be safely managed by titrating drug to the target dose. For example, in the gantenerumab studies, titrating to the target dose reduced ARIA-E incidence in both APOE4 carriers and non-carriers and the majority of episodes were asymptomatic. Other studies have suggested that APOE4 carriers are at higher risk for ARIA-E. While ARIA-E appears to be manageable, uncertainty remains about whether even a minimal risk could be problematic for preclinical AD patients, or whether ARIA-E occurs less frequently in earlier stages of disease or in individuals with lower levels of vascular amyloid.

Although it may be challenging, it will be necessary to develop criteria that could be used in primary care settings for safely beginning treatment and monitoring

for ARIA-E should an anti-Aβ monoclonal antibody treatment be approved for AD. A better understanding of the mechanisms involved could relieve concerns among primary care physicians once these therapies become available.

## Interim and futility analyses are useful only if appropriately designed

Futility analyses are designed to protect participants from unnecessary exposure to drugs that have little chance of providing benefits, but if they result in premature termination of a trial, participants and sponsors alike – indeed, the entire field – may suffer adverse consequences from a failure to identify efficacious treatments and the failure to collect a complete dataset from the trial (19). The aducanumab Phase 3 program is not the only example in the field in which interim analysis wrongly predicted futility, raising questions about the design and appropriateness of futility analyses.

Among the fundamental tenets of futility analyses is that participants included in the analysis are representative of those in the full dataset and that drop-outs are equally distributed across all treatment groups. Protocol amendments made in the course of the aducanumab study, however, resulted in non-identical interim and final populations and in cohorts that had received different doses for different periods of time

All futility analyses come with a price: loss of statistical power to demonstrate efficacy. This cost must be carefully weighed against any benefits from early termination. While there are clear advantages to stopping early when failure is inevitable, the possibility of misleading futility analyses suggests that criteria for defining failure versus success need to be very carefully specified. To implement criteria for interim analyses requires a better understanding of the clinical-biological trajectories of disease progression in stratified patient populations (19, 20). Interim analyses could also benefit from looking at the totality of evidence and by aggregating signals to reduce noise.

## Responder analyses could help identify subgroup differences

To determine the disease stage at which a treatment may be efficacious, the optimal duration of treatment, and other patient characteristics that may affect efficacy, responder analyses of trial data and data from open-label extension studies can be valuable. Post-hoc exploratory data analyses may yield improved understanding of study results and inform the design of future studies. For example, in the SCarlet RoAD study of gantenerumab, an exploratory analysis that classified participants according to whether they were slow or fast progressors suggested
that fast progressors showed a greater exposure-
dependent slowing of clinical and cognitive decline with
treatment (8). While not a classic responder analysis,
the exploration of the faster progressing subset allowed
modeling related to a drug-placebo difference and helped
to define inclusion criteria for the ongoing Phase 3
GRADUATE program with higher dose of gantenerumab.

Moving forward with amyloid-based therapies

Genetic, neuropathologic, biochemical, and now
clinical trials support the amyloid hypothesis of AD while
recognizing that downstream pathological processes
contribute importantly to the development of the disease
(6). Many questions remain to be answered in order
to translate the amyloid hypothesis into efficacious
therapies. For example, further research is needed to
determine which Aβ species are most important to target,
whether relevant Aβ species change over the course
of disease, if there is an optimal time for targeting a
particular Aβ species, and whether at some point amyloid
becomes less relevant or irrelevant. Developing a larger
repertoire of biomarkers to predict disease onset and
progression, e.g. microglial activation biomarkers, may
help clarify the role of amyloid-related mechanisms as
well as other mechanisms in disease progression (21).
Preliminary data from the monoclonal antibody trials
suggest there are "downstream" effects on cerebrospinal
fluid levels of neurofilament light, neurogranin, and tau.
These may be crucial measures of the biological effects of
interventions and that can eventually be compared across
trials.

An effective treatment may also require an
Aβ-targeting drug in combination with a drug targeting
another mechanism (e.g. neuroinflammation) or two
drugs that target different amyloid mechanisms (e.g.
production and clearance of Aβ) (22). Investigators have
explored targeting Aβ in combination with tau, the
protein found in the neurofibrillary tangles that along
with amyloid plaques represent the major pathological
hallmarks of AD. Moving this approach forward,
however, will require a better understanding of the value
of various tau-related targets, the relationship of amyloid
to the level of tau burden as well as the time lag between
amyloid deposition, tau deposition, and cognitive
impairment (23). Employing tau PET studies in clinical
trials may help define these aspects of the role of tau in
AD (24, 25). Other tau biomarkers are in development.
For example, Walsh and colleagues have shown that an
N-terminal fragment of tau (NT1) and p-tau in plasma
are significantly increased in AD and mild cognitive
impairment (MCI) (26).

Analysis of data from several failed clinical trials of
amyloid-targeting drugs suggest that to slow or prevent
disease progression, it may be necessary to intervene
at very early, pre-symptomatic stages of the disease
(27, 28). Studies currently underway to test this include

the A4 study in clinically normal older individuals
with elevated amyloid levels on screening PET; and
the AHEAD 3-45 study in clinically normal individuals
with elevated or intermediate amyloid. Other prevention
trials are underway in clinically normal participants at
increased genetic risk of developing AD, including the
Alzheimer's Prevention Initiative (API) Colombia Trial
(20). [The DIAN-TU studies involving both clinically
normal and symptomatic autosomal dominant mutation
carriers recently reported negative topline results.] The
challenges inherent in these prevention trials include
the difficulty of detecting a slowing of progression in
cognitively normal individuals and the resulting large
sample size and long trial durations required; the hope of
preventing AD has motivated many individuals around
the world to volunteer for these studies.

Very early intervention, including primary prevention,
may be more feasible with active vaccination or oral
therapy rather than passive immunotherapy requiring
repeated intravenous or subcutaneous administration.
Active vaccination against Aβ remains a plausible
strategy (e.g. CAD-106; UB-311). Orally bioavailable
BACE inhibitor programs have been halted with concern
about observations of cognitive worsening in trials;
however, evidence that this cognitive toxicity is dose-
related and reversible raises hope that viable regimens
may eventually move forward.

Conclusions

The termination of multiple clinical trials for futility
or adverse events has had a major impact on the AD
clinical research enterprise. However, evidence strongly
supports amyloid as a viable target although not the only
important target. Given the complexity of AD pathology,
combination treatment will likely be needed. If antibody
trials are sufficiently positive, they could represent a
good first step towards combination treatment and lead
to financial coverage and use of amyloid PET, which
would be a major advance for the clinical care of AD.

To optimize the potential benefits and reduce the
potential risks to participants as much as possible,
methodological improvements in the design and conduct
of clinical trials are needed. For example, adaptive dose
finding studies may result in more patients assigned
to an effective dose and avoid exposure of patients to
ineffective doses. In addition, since disease modification
depends on protecting neurons from the pathology, a
better understanding of neuroprotection, the relationship
of the biological underpinnings of the aging process
(30), and the development of intermediate biomarkers of
neuroprotection are needed. Advancing understanding
of the complexity underlying the development of AD
and potential interventions that could slow or halt the
disease pathophysiological progression will require
more discovery science as well as increased use of
platform trials. Public-private partnerships with strong
collaborations and data sharing will be necessary to
accelerate these efforts, along with broad public
engagement.

***Acknowledgements:*** The authors thank Lisa J. Bain for assistance in the preparation of this manuscript.

**Conflicts of interest:** The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Aisen reports grants from Janssen, grants from NIA, grants from FNIH, grants from Alzheimer's Association, grants from Eisai, personal fees from Merck, personal fees from Biogen, personal fees from Roche, personal fees from Lundbeck, personal fees from Proclara, personal fees from Immunobrain Checkpoint, outside the submitted work; Dr Cummings is a consultant for Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP Pharma, Eisai, Foresight, Gemvax, Green Valley, Grifols, Karuna, Nutricia, Orion, Otsuka, Probiodrug, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, United Neuroscience pharmaceutical and assessment companies, and the Alzheimer Drug Discovery Foundation; and owns stock in ADAMAS, BioAsis, MedAvante, QR Pharma, and United Neuroscience. Dr. Doody is an employee of Genentech/F Hoffman-LaRoche and holds stock in the company; Dr. Kramer is an employee of Eisai Company, Ltd. Dr. Kramer is an employee of Eisai Company Ltd; Dr. S. Salloway: NC; Dr. Selkoe: NC; Dr. Sims reports other from Employee of Eli Lilly and Company, outside the submitted work; Dr. Sperling reports personal fees from AC Immune, personal fees from Biogen, personal fees from Janssen, personal fees from Neurocentra, personal fees from Eisai, personal fees from GE Healthcare, personal fees from Roche, personal fees from InSightec, personal fees from Takeda Pharmaceuticals, grants from Eli Lilly, grants from Janssen, grants from Digital Cognition Technologies, grants from Eisai, grants from NIA, grants from Alzheimer's Association, personal fees and other from Novartis, personal fees and other from AC Immune, personal fees and other from Janssen, outside the submitted work; 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.

**Open Access:** This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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