Incremental Value of Plasma Biomarkers in Predicting Clinical Decline Among Cognitively Unimpaired Older Adults: Results from the A4 trial

Objective: To evaluate the predictive utility of baseline plasma biomarkers and neuropsychological measures in identifying cognitively unimpaired older adults at risk of cognitive and functional decline over five years. Background: The clinical and biological heterogeneity observed in Alzheimer disease (AD) complicates design of trials and the identification of appropriate participants. Identifying practical tools to define more homogenous subgroups could enhance clinical trial enrichment and improve early detection. Methods: We analyzed data from the Anti Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) trial and its companion Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study. The sample included 866 cognitively unimpaired, amyloid positive individuals from the A4 trial (comprising participants randomized to receive Solanezumab or placebo) and 343 cognitively unimpaired, amyloid negative individuals from LEARN. Cognitive/functional decline was defined as an increase of at least 0.5 in Clinical Dementia Rating Global Score (CDR GS) during a 240 week period. Using multiple logistic regression models, we evaluated the predictive value of demographic variables, APOE4 status, amyloid PET SUVR, plasma P-tau217, and Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS PACC) in three groups: A4 Solanezumab, A4 Placebo and LEARN. In a substudy including 656 participants with available data, we assessed the incremental value of additional plasma biomarkers (AB42/AB40 ratio, GFAP, and NfL). Results: Both plasma P-tau217 and ADCS PACC significantly improved predictive performance over a base model with demographics and APOE4. The full model combining all predictor variables yielded the highest AUCs across A4 Solanezumab (0.80 +/- 0.06), A4 Placebo (0.80 +/- 0.06), and LEARN (0.78 +/- 0.08). Adding other plasma biomarkers yielded small but consistent improvements in AUC (1 to 3%). Conclusions: Plasma Ptau217 and ADCS PACC, individually and in combination, improved prediction of cognitive/functional decline in asymptomatic older adults. Predictive models incorporating these scalable and non invasive measures improved clinical trial enrichment and earlier identification of at risk individuals preclinical AD.