# Alzheimer's Prevention Initiative ADAD Colombia Trial Program

> **NIH NIH R01** · BANNER HEALTH · 2024 · $4,541,398

## Abstract

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-treat...

## Key facts

- **NIH application ID:** 10855439
- **Project number:** 1R01AG086363-01
- **Recipient organization:** BANNER HEALTH
- **Principal Investigator:** Robert C Alexander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $4,541,398
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855439

## Citation

> US National Institutes of Health, RePORTER application 10855439, Alzheimer's Prevention Initiative ADAD Colombia Trial Program (1R01AG086363-01). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10855439. Licensed CC0.

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