Sex, Education and Race/ethnicity Have Distinct Effects on Amyloid and Tau‐pet Status

Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self-reported sex, educational attainment and race/ethnicity on amyloid-positivity, and tau-PET-positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Logistic generalized estimating equations were used to estimate frequency of amyloid-positivity (using cohort-specific thresholds for amyloid-PET [84%] or CSF) and tau-PET-positivity (cohort-specific thresholds of 2SD above mean temporal uptake in amyloid-negative controls). We assessed: i) sex and APOEε4 ( N  = 10,098) associations, to complement earlier findings of a higher frequency of tau-positivity in females, ii) effects of lower/higher education ( N  = 10,970; cohort-specific median-split), and iii) effects of race/ethnicity (non-Hispanic White [hereafter: White], N  = 4880; Asian, N  = 116; Black or African-American [hereafter: Black], N  = 353; Hispanic, N  = 356, only from Northern-American cohorts). Outcomes were frequency of amyloid-positivity in CU individuals only, and tau-PET-positivity in both amyloid-positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau-positivity were assessed and only retained in the models when significant. Female sex was associated with an APOEε4 -independent increased frequency of amyloid-positivity (β=0.51[0.22], p  = 0.02) in CU and increase of tau-positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p  <0.01). Remarkably, tau-positivity frequencies of female APOEε4 non-carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid-positivity frequency (β=-0.12[0.05], p  = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau-positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p  <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non-White groups compared to White (Hispanic:β interaction =-0.05[0.01], p  <0.01; Black:-0.04[0.01], p  <0.01; Asian:-0.02[0.01], p  = 0.04). This suggests that the impact of age on amyloid-positivity was less pronounced in non-White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau-positivity frequency than White (β=0.51[0.22], p  = 0.02; Figure 3). In this multi-center initiative comprised of clinical and community-based cohorts, we observed that self-reported sex, educational attainment and race/ethnicity were related to positivity-frequencies of Alzheimer's disease pathology.