Plasma P-tau217, APOE Genotype, and the Timing of Cognitive Impairment in individuals Across Diverse Racial and Ethnic Groups: A Pooled Analysis of Prospective Cohort Studies

Abstract

ABSTRACT/SUMMARY Background: Plasma phosphorylated tau217 (P-tau217), a biomarker of Alzheimer’s disease (AD), can increase before overt symptoms. However, individuals with similar P-tau217 levels but different genetic backgrounds might differ in their risk or timing of cognitive decline. We aimed to determine whether APOE genotype provides additional prognostic information beyond plasma P-tau217 for estimating the risk and timing of cognitive impairment. Methods: We did a pooled analysis of participant-level data from seven multi-ethnic prospective cohorts of older adults spanning the Alzheimer’s disease clinical spectrum, from cognitively unimpaired individuals at elevated risk to those with mild cognitive impairment or dementia, at sites in the USA, Canada, and the Dominican Republic. Data were collected from 1992 through 2025. The primary outcome was cognitive impairment, defined as mild cognitive impairment or dementia. Baseline analyses included all eligible participants (those with data for plasma P-tau217, clinical diagnosis, APOE genotype, and required covariates); longitudinal analyses were restricted to participants who were cognitively unimpaired at baseline and had at least one follow-up clinical assessment. We evaluated whether APOE-ε4 carrier status modifies the risk and timing of cognitive impairment associated with continuous plasma P-tau217. Associations of baseline P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by APOE-ε4 and with interaction terms. Timing and prognostic performance were evaluated using survival analyses, discrimination measures, and random survival forests. Findings: Among 8,873 participants with available plasma P-tau217 and clinical data who were examined for eligibility, 8,582 participants (5,652 female and 2,930 male) were included in, the baseline analysis. Of these, 4,569 participants (3,173 female and 1,396 male) were cognitively unimpaired at baseline and were included in the longitudinal analysis. Increase in P-tau217 levels was associated with cognitive impairment at baseline and with incident cognitive impairment in APOE-ε4 carriers compared to non-carriers (OR = 2.25, 95% CI 1.52–3.34 vs 1.52, 95% CI 1.35–1.72; HR = 1.76, 95% CI 1.36–2.26 vs 1.26, 95% CI 1.12–1.42, for 1-SD increase of P-tau217 levels). Each 1-SD increase in P-tau217 levels was accompanied by a 24% shorter period to cognitive impairment among APOE-ε4 carriers, compared to 13% among non-carriers. Differences in cognitive-impairment-free survival by P-tau217 level emerged three to four years before symptom onset. Interpretation: Plasma P-tau217 levels, considered together with APOE genotype, may help stratify risk and estimate the timing of future cognitive impairment in asymptomatic individuals who are at elevated risk for Alzheimer’s disease, such as those with a family history of dementia or known APOE-ε4 carrier status. These findings support the use of biomarker-informed approaches to guide monitoring and therapeutic intervention in appropriately selected at-risk individuals before the onset of clinical symptoms.