Project Summary/Abstract
There is an urgent need to find effective preclinical Alzheimer's disease (AD) treatments as quickly as
possible. We established the Alzheimer's Prevention Initiative (API) to help launch a new era in AD prevention
research, evaluating promising investigational preclinical AD treatments in people who, based on their genetic
background and age, are at extremely high risk of progression to the clinical stages of AD, and helping to
establish the biomarker and cognitive endpoints and accelerated regulatory approval pathway needed to rapidly
evaluate new treatments. Our original API autosomal dominant AD (ADAD) grant proposed to prepare for and
conduct the first stage of a 5-year, randomized, double-blind, placebo-controlled trial of an anti-amyloid agent in
200 cognitively unimpaired Presenilin 1 (PSEN1) E280A mutation carriers and placebo treated in 100 non-
carriers (NC) from the world's largest ADAD kindred in Colombia. Outcomes include a sensitive composite
cognitive endpoint and the best established brain imaging and cerebrospinal fluid (CSF) biomarkers of AD. Other
goals are to clarify whether the treatment's biomarker effects are reasonably likely to predict later clinical benefit
and help qualify them as surrogate endpoints under the FDA's accelerated approval pathway and provide a
better test of the amyloid hypothesis. The grant received an outstanding priority score in 2012, permitted us to
select our industry partner, Genentech, and its promising anti-amyloid antibody, crenezumab, garner $15M from
philanthropy and the majority of funding from Genentech, and establish a novel agreement to share data and
biological samples after the trial. Our subsequent proposal for another preclinical trial of both an active
immunotherapy against amyloid and a medication to reduce its production (a BACE inhibitor) in cognitively
unimpaired APOE4 homozygotes also received an outstanding priority score and secured NIH, Novartis/Amgen,
and philanthropic support. API has created exceptionally large registries along the way to support enrollment in
these and other trials. Our API ADAD trial was launched in 2013 and is going well; enrollment is expected to end
in late 2016 and the trial will end in 2021. Our original aims were to prepare for and launch the first stage of
this preclinical ADAD/biomarker development trial; clarify whether crenezumab's biomarker effects are related
to a subsequent clinical benefit, explore the extent to which baseline biomarkers are associated with a differential
response to treatment or subsequent cognitive decline in the absence of treatment; and eventually create a user-
friendly public resource of preclinical AD trial data and biological samples after the trial is over. Our Current API
ADAD Grant Aims are to 1) address the original aims, 2) Extend blinded treatment for those enrolled earliest in
the to increase power to detect cognitive benefit, complete the trial, and address the original aims in a manner
that provides the greatest benefit to the field; 3) Acquire tau PET images at the participants' 30 and 60 month
visits and clarify their ability to predict clinical benefit and course; 4) Provide a secure and robust data repository
along with the data search and visualization tools to support the most productive, prevalent, and appropriate use
of data after the trial is over; and 5) Establish the infrastructure needed to share biological samples in the most
productive and appropriate way. The proposed grant will help API investigators oversee the trial until its
completion, analyze and report the data, incorporate and clarify the theragnostic value of tau PET images, and
develop the infrastructure to share data and biological samples, aims that will not be funded by Genentech (nor
our new APAI ADAD partner, Roche). This is an extremely inclusive project, having been vetted by leading
academic and community stakeholder advisors, and representatives from the NIA, FDA, European Medicines
Agency, and pharmaceutical research companies.