First NIH-supported Alzheimer's prevention trial in PSEN1 carriers reported

Evidence before this study

We searched PubMed and Embase for articles published in English and other languages from Jan 1, 2010, to Sept 30, 2025, using combinations of Medical Subject Headings and the free-text terms “Alzheimer's”, “autosomal dominant Alzheimer's disease”, “prevention”, biomarker”, “surrogate biomarker”, “composite cognitive test scores”, “Alzheimer's disease biomarkers”, “amyloid”, “regulatory policy”, and “data sharing”. Our review of the existing literature was further informed by private meetings with pharmaceutical companies; symposia and scientific conferences; discussions with researchers affiliated with the Alzheimer's Prevention Initiative (API), Dominantly Inherited Alzheimer's Network, the Alzheimer's Clinical Trials Consortium (ACTC), and the Collaboration for Alzheimer's Prevention; and other meetings. At the time of conception of the API autosomal-dominant Alzheimer's disease (ADAD) Colombia Trial, the approved treatments for established Alzheimer's disease dementia showed only modest efficacy and did not change the disease course. Contemporary clinical trials in preclinical Alzheimer's disease were not feasible due to the need for large sample sizes, long follow-up periods to show an effect, and sensitive assessment tools capable of discerning cognitive decline in people who are at risk who do not have cognitive impairment and biomarkers that can be used to predict and monitor disease progression.

Added value of this study

We conducted this trial to establish whether the prevention or delay of the clinical onset of Alzheimer's disease was possible, as assessed with clinical and biomarker outcomes, in a homogeneous population of cognitively unimpaired individuals from an extended Colombian kindred carrying a single autosomal-dominant mutation in the PSEN1 gene (Glu280Ala). This trial was the first National Institutes of Health-supported trial of a putative Alzheimer's disease-modifying treatment in cognitively unimpaired participants predisposed to the clinical onset of Alzheimer's disease. It was conducted in the world's largest known ADAD kindred affected by a single Alzheimer's disease-causing mutation and helped set the stage for other prevention trials to follow.

Implications of all the available evidence

Robust fibrillar amyloid removal appears necessary to achieve clinical efficacy in people who already have elevated brain amyloid. Our results do not rule out the possibility that different anti-oligomeric agents could confer benefit. Our trial also introduced new strategies to evaluate and support the potential approval of drug therapies in cognitively unimpaired people at biological risk for Alzheimer's disease and a precedent-setting agreement to share trial data and samples to further inform the study of preclinical Alzheimer's disease and the design of future trials.

Source: The Lancet Neurology