Rosa‐Neto, Pedro

Abstract Background 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. Method 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. Result 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). Conclusion 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.

Abstract Background Studies suggest that sex influences the deposition of tau in the human brain and impacts on the relationship of tau with AD‐related outcomes. The aim of this study is to evaluate the extent to which sex influences PET‐Tau related outcomes and whether this effect is related to specific tau PET tracers. Method We assessed 456 participants from the HEAD study (mean age = 66.07 ± 13.05). All individuals had available Tau‐PET with Flortaucipir and MK6240, Aβ‐PET and a subset had plasma p ‐Tau 217 ( n = 352). We conducted a linear regression analysis between sex and PET Tau to evaluate the direct influence of sex on PET Tau SUVR. Next, we assessed whether sex affected the relationship between Tau PET (in BRAAK I‐II, III‐IV, V‐VI regions) and Aβ‐PET or plasma p ‐Tau 217 by adding an interaction term in the associations. All analyses were corrected by age, clinical classification, and amyloid burden. Result No significant differences were observed between male and female SUVR levels in either Flortaucipir and MK6240 tracers (Figure 1). However, when assessing the relationship between Aβ‐PET and Tau, a statistically significant interaction with sex was seen between MK6240 in BRAAK III‐IV (β = 0.160, p = 0.020 ; Figure 2) and BRAAK V‐VI regions (β = 0.196, p = 0.008; Figure 2), with women having a stronger association. Furthermore, we found an interaction between sex and p ‐tau217 on Tau PET SUVR in BRAAK regions I‐II using MK6240 or Flortaucipir (β = ‐0.184, p = 0.014; β = ‐0.266, p = 0.002; Figure 3) indicating that women present a weaker relationship between p ‐tau217 and Tau PET. Conclusion Our results did not show any differences between men and women in Tau‐PET SUVR uptake across tau tracers. However, we found that sex affected how Aβ‐PET and plasma p ‐tau217 were associated with Tau‐PET uptake. Further studies are needed to elucidate the underpinnings of the link between sex and the association between these biomarkers.