Plasma Phosphorylated Tau 217 Percentage by Race and Ethnicity in Preclinical Alzheimer Disease

Importance In trials targeting preclinical Alzheimer disease (AD), defined as amyloid pathology without cognitive symptoms, racial and ethnic differences in plasma phosphorylated tau 217 percentage (%p-tau217) may influence screening eligibility. Objective To characterize racial and ethnic differences in %p-tau217 and determine whether associations between %p-tau217, cognition, and amyloid positron emission tomography (PET) differ across groups. Design, Setting, and Participants This was a cross-sectional analysis of AHEAD 3-45 screening participants conducted from July 2020 to October 2024 at 106 sites across 4 world regions. Adults aged 55 to 80 years with %p-tau217 measured before medical and cognitive exclusions (N = 15 612) were included. Exposures Self-reported race (Asian, Black, and White) and ethnicity (Hispanic and non-Hispanic) and apolipoprotein E ε4 ( APOE ε4) carrier status. Main Outcomes and Measures %p-tau217 levels and associations of %p-tau217 with Preclinical Alzheimer Cognitive Composite 5 (PACC5) score and amyloid PET were evaluated across racial and ethnic groups using multivariable linear regression. Results Among 15 612 participants, the mean (SD) age was 68.4 (6.2) years; 9941 (63.7%) were female and 5755 (36.9%) were APOE ε4 carriers. %p-tau217 levels were lower among Asian, Black, and Hispanic participants than among White and non-Hispanic participants. APOE ε4 status was associated with higher %p-tau217 across all groups. The association between APOE ε4 status and %p-tau217 differed by race ( APOE ε4 × race: F 2,14 973 = 10.06; P < .001) and ethnicity ( APOE ε4 × ethnicity: β, 0.042; 95% CI, 0.017 to 0.067; P = .005) (Asian: β, 0.05; 95% CI, 0.02 to 0.08; P = .01; Black: β, 0.05; 95% CI, 0.03 to 0.08; P = .002; Hispanic: β, 0.04; 95% CI, 0.02 to 0.07; P = .005). The %p-tau217–PACC5 association showed no pairwise differences across racial groups but differed by ethnicity (β, −0.53; 95% CI, −0.85 to −0.21; P = .008) and APOE ε4 × ethnicity (β, 0.78; 95% CI, 0.26 to 1.30; P = .02). The %p-tau217–PET association showed no significant pairwise differences across racial groups but differed by ethnicity (β, −6.30; 95% CI, −9.10 to −3.51; P < .001) and APOE ε4 × ethnicity (β, 7.12; 95% CI, 2.52 to 11.73; P = .01). Conclusions and Relevance In this cross-sectional study, plasma %p-tau217 varied across racial and ethnic groups. Consistent %p-tau217–PACC5 score and %p-tau217–PET associations across racial groups support plasma-based screening before PET confirmation, while ethnicity-related findings warrant further investigation.