The Alzheimer's Prevention Initiative (API) was established to rapidly evaluate investigational preclinical Alzheimer's disease (AD) treatments in cognitively unimpaired people who, based on their genetic background and age, are at the highest imminent risk for clinical progression, to help advance a new era in AD prevention research, and to find treatments that work as soon as possible. This application seeks five years of partial support for the initial stag of a 104-260 week multi-center randomized clinical trial of an investigational amyloid-? (A?) modifying treatment in 650 cognitively unimpaired 60-75 year-old apolipoprotein E (APOE) ?4 homozygotes (HMs) using the best established cognitive, brain imaging and cerebrospinal fluid (CSF) measurements of preclinical AD. The primary outcome is change in an empirically predefined composite cognitive test score. Other outcomes include changes in volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG PET) regional cerebral metabolic rate for glucose (rCMRgl), flutemetamol PET fibrillar A?, and CSF A?42, total tau (t-tau) and phospho-tau (p-tau) measurements. Adaptive elements include serial futility assessments, a 104-week interim analysis, and data and safety monitoring board (DSMB)-facilitated decisions about study continuation, study expansion, and the evaluation of other at-risk groups. Exploratory analyses will determine whether the treatment's 24-month treatment effects are related to the treatment's clinical effects and whether biomarker evidence of less extensive disease is associated with a greater therapeutic response. This study complements API's funded trial in autosomal dominant AD (ADAD) mutation carriers. It capitalizes on our longstanding efforts to characterize the preclinical biomarker and cognitive changes in APOE ?4 HM, heterozygotes (HTs) and noncarriers (NCs), several of the API's established policies, procedures, and collaborative relationships, its data and sample-sharing paradigm and growing Alzheimer's Prevention Registry, and at least $50 million in additional industry and philanthropic funding. Our potentially license-enabling APOE ?4 and ADAD mutation carrier trials have been vetted by leading academic, industry, NIA, regulatory agency, and community stakeholders. The project's aims: to evaluate an investigational A?-modifying treatment in unimpaired HMs, to provide a better test of the amyloid hypothesis, to determine whether to evaluate the treatment in others at risk for late-onset AD, to help clarify the extent t which a treatment's biomarker effects may predict a clinical response and qualify as "reasonably likely" surrogate endpoints in future preclinical trials, to provide information about the impact o APOE genetic test disclosure in this new era of AD prevention research, to provide a public resource of data and samples after the trial is over, and to complement and support other research programs related to the evaluation of preclinical AD treatments. The project is intended to help find effective preclinical treatments for late-onset AD as soon as possible.
In this therapeutic trial, the Alzheimer's Prevention Initiative (API) will evaluate a promising anti-amyloid treatment in healthy older adults with two copies of the APOE4 gene, the major genetic risk factor for late- onset Alzheimer's disease (AD). It is intended to complement API's funded trial in carriers of a rare AD causing mutation, to help test the leading AD theory, to help determine whether to evaluate the treatment in other individuals at risk for developing AD, to help establish the measurements needed to rapidly test the range of promising prevention therapies, to provide an important resource of data and biological samples for the scientific community, and to help find effective prevention therapies as quickly as possible.