The Ante-Amyloid Treatment of Alzheimer's disease (A3) Trial and Alzheimer Plasma EXtension (APEX) Study - SUMMARY: This R01 application is to continue NIH funding for the Ante-Amyloid treatment of Alzheimer’s disease (A3) Trial and the Alzheimer Plasma Extension (APEX) Study. The A3 Trial is one of the sister trials of the AHEAD 3-45 Study testing lecanemab, a potent amyloid-removing monoclonal antibody, at the asymptomatic or “preclinical” stage of AD. The overall goal of these studies is to build a “bridging chain of evidence” that will link the removal of very early amyloid-beta (Aβ) to slowing the spread of early AD tauopathy and ultimately to the prevention of cognitive decline that occurs in the later stages of AD. The A3 testing is low dose lecanemab, prior (“ante”) to elevated brain amyloidosis, defined by intermediate levels (20-40 Centiloids) on screening Aβ PET. A3 runs in parallel with “A45” Trial, testing higher dose lecanemab in participants at later stages of preclinical AD (>40CL). The A3 Trial is the first prevention trial to test an amyloid-lowering therapeutic at the intermediate amyloid stage of sporadic AD and will contribute essential knowledge about the optimal window for efficacy and safety of anti-amyloid monotherapy. A3 is primarily an imaging and biofluid Phase IIb Study at a very early stage of AD pathophysiology, and will require longer term cognitive and functional assessments, paired with biofluid and imaging outcomes, through the Open-Label Extension. This A3 evidence will serve to elucidate the links between Aβ, tau, and the cognitive decline expected at the later preclinical stages studied in the A45 trial. The AHEAD 3-45 Study screened over 20,000 individuals ages 55- 80, and recently completed randomization of (N=441) and A45 (N=1146), utilizing a novel plasma screening algorithm. The APEX Study, funded as a supplement to the A3 R01, will follow 1000 participants with subtle plasma abnormalities, but were not eligible for randomization due to amyloid PET below the A3 threshold (<20CL). APEX is oversampling from a large group of individuals from minoritized racial and/or ethnic underrepresented groups (URG), who showed disproportionate rates of ineligibility on screening Aβ and tau markers. APEX (currently >50% URG enrollment) provides an unparalleled opportunity to evaluate longitudinal trajectories of AD biomarkers across ethnoracial groups to inform future primary AD prevention trials. Furthermore, across APEX and A3-45, we will evaluate Social Determinants of Health, and novel markers of vascular and inflammatory processes to evaluate independent (and Aβ interactive) contributions to cognitive decline. This will lay the foundation for future prevention trials in more representative populations in whom Aβ may not be the primary driver of dementia. Completing these public-private-philanthropic ACTC partnership projects will provide critical information to the field, in particular whether lowering Aβ at this much earlier stage of disease can halt the spread of tauopathy and have a greater impact on cognitive decline. These studies will serve to chart the path forward towards primary prevention of AD, as well as combination prevention trials to address the multiple contributors to cognitive decline in older individuals.
