Plasma GFAP for populational enrichment of clinical trials in preclinical Alzheimer’s disease

Alzheimers Dement. 2025 May;21(5):e70209. doi: 10.1002/alz.70209.

ABSTRACT

INTRODUCTION: Cognitively unimpaired (CU) amyloid beta (Aβ)+ individuals with elevated plasma glial fibrillary acidic protein (GFAP) have an increased risk of Alzheimer’s disease (AD)-related progression. We tested the utility of plasma GFAP for population enrichment CU populations in clinical trials.

METHODS: We estimated longitudinal progression, effect size, and costs of hypothetical clinical trials designed to test an estimated 25% drug effect on reducing tau positron emission tomography (PET) accumulation in the medial temporal lobe (MTL) and temporal neocortical region (NEO-T).

RESULTS: CU GFAP+/Aβ+ individuals present an increased annual rate of change and effect size in tau PET_MTL and tau PET_NEO-T compared to the other groups. An enrichment strategy selecting CU GFAP+/Aβ+ individuals would require a smaller sample size (≈ 57% reduction) and fewer Aβ PET scans (≈ 74% reduction) than trials enriched with Aβ PET alone, reducing total clinical trial costs by up to 64%.

DISCUSSION: Our results suggest that clinical trials focusing on preclinical AD recruiting Aβ+ individuals with elevated GFAP levels would improve cost effectiveness.

HIGHLIGHTS: Cognitively unimpaired (CU) glial fibrillary acidic protein (GFAP)+/amyloid beta (Aβ)+ shows increased changes in tau positron emission tomography (PET) . CU GFAP+/Aβ+ enriched clinical trials require a reduced sample size compared to Aβ+ only. CU GFAP+/Aβ+ enrichment reduces Aβ PET scans required and costs. CU GFAP+/Aβ+ enrichment allows the selection of individuals at early stages of the Alzheimer’s disease continuum.

PMID:40346617 | DOI:10.1002/alz.70209