Alzheimer's Prevention Initiative ADAD Colombia Trial Program

Project Summary/Abstract When the API Autosomal Dominant Alzheimer's Disease (ADAD) Colombia Trial (NCT01998841) was announced in 2012, it launched a new era in AD prevention research. The trial led us to identify ~6,000 persons from the world's largest ADAD kindred, including nearly 1,200 presenilin 1 (PSEN1) E280A mutation carriers,

who are virtually certain to develop AD and become cognitively impaired at 44 (SD ± 5) years of age; establish the clinical trials, infusion capability, PET, and MRI infrastructure Colombia needed to conduct interventional studies in the kindred; and introduce precedent setting scientific, ethical, social support, and logistical paradigms

as well as pioneering sample sharing agreements. Moreover, it demonstrated the ability to evaluate an experimental treatment in a vulnerable population from a developing country in ways that the participants valued, such that 94% of participants completed the 5-8-year trial. In recent landmark pivotal trials, the Aβ plaque-clearing

antibody (PCA) treatments lecanemab and donanemab were associated with a significant clinical benefit in mildly impaired late-onset AD (LOAD) patients, with dramatic Aβ PET and plasma pTau reductions, and significant effects on other Aβ, tau, neurodegenerative, and inflammatory (A/T/N/I) biomarkers. These data provided

compelling support for the role of Aβ aggregates in the development, treatment, and prevention of AD and support the use of biomarker endpoints that are likely to be associated with a clinical benefit. Here, we propose to conduct a two-part clinical trial in 200 cognitively unimpaired and mildly impaired PSEN1 mutation carriers

and 40 placebo-treated non-carriers from this remarkable kindred. In Part 1, carriers will receive up to 18 months of a plaque-clearing antibody (PCA) treatment (exemplar: donanemab), permitting us to compare the magnitude of Aβ PET and plasma pTau reductions in this ADAD kindred to that observed in trials of the same drug in Aβ+

mildly impaired LOAD patients and cognitively unimpaired older adults. In Part 2, carriers will be randomized to receive 1) continued PCA treatment, 2) an oral gamma secretase modulator (GSM) treatment (exemplar: RG6289) with the potential to minimize the re-accumulation of Aβ aggregates in a complementary, potentially

less expensive, and more scalable way, 3) combined PCA/GSM treatment, and 4) placebo treatment for 18 months. This seamless, double-blind, placebo-controlled, double-dummy study of a PCA and a GSM in cognitively unimpaired and MCI/mild AD PSEN1 E280A mutation carriers will efficiently address a number of key

questions including (1) determining the efficacy of a PCA in reducing brain amyloid levels in ADAD; (2) examining the relative efficacy of combination treatment following PCA treatment versus PCA monotherapy versus GSM monotherapy versus placebo to further lower or maintain low brain amyloid levels as well as on downstream

biomarkers; (3) estimating how long placebo-treated mutation carriers remain amyloid negative following PCA- induced amyloid clearance; (4) providing a foundation for understanding the longer term clinical impact of the interventions leveraging the Colombian API Registry; and (5) providing invaluable data and samples for the field.