APOE ε4 carriership status enhances age-related changes in Alzheimer’s disease plasma biomarkers concentrations

Alzheimer’s disease (AD) plasma biomarkers are cost-effective tools to detect early stage amyloid pathology. We investigated how interactions between AD genetic risk (apolipoprotein E (APOE) ε4, AD polygenic risk score (excluding APOE; PRSAD)), age, and sex affected AD plasma biomarkers concentrations in a population-based cohort. We included 5913 participants from the Netherlands Twin Register age 30 – 80 (64.1% females, 29.8% ε4 carriers) and measured plasma phosphorylated-tau-217 (p-tau217), amyloid-β−42/40 (Aβ−42/40), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We showed that the PRSAD did not associate with biomarker concentrations over age. In ε4 carriers, decreases in Aβ−42/40 became steeper after age 50, and increases in p-tau217 and GFAP became steeper after age 55 and 60 compared to non-carriers, respectively. Analyses in a separate longitudinal cohort (EMIF-AD) confirmed that p-tau217 concentration changes in ε4 carriers reflect AD pathology. These results highlight the potential of plasma biomarkers, especially p-tau217, for early detection of preclinical AD pathology. In cognitively normal individuals, the rate of change in concentrations of plasma ptau217 and Aβ−42/40 over age differs between APOE ε4 carriers and non-carriers. For p-tau217, the effect of APOE ε4 carriership is stronger in males than females.