Lower Antemortem [ ¹⁸ F]flortaucipir PET retention in Males and Older Individuals is Explained by Lower Postmortem Tau Tangle Density

Abstract Background Older age and male sex have been associated with lower Tau‐PET uptake in symptomatic Alzheimer's disease. We investigated the PET‐to‐neuropathological correlates of age‐ and sex‐effects on tau in independent PET ( N = 680), autopsy ( N = 947), and PET‐to‐autopsy ( N = 84) analyses. Method Tau‐PET‐analyses included amyloid‐positive participants with MCI or dementia who underwent [ 18 F]flortaucipir‐PET. Autopsy‐analyses included MCI or dementia cases with moderate‐to‐frequent CERAD scores and available Braak and tangle density data. PET‐to‐autopsy‐analyses included cases who had undergone Tau‐PET during life, died, and had undergone autopsy, including Braak staging (PET‐to‐post‐mortem‐interval: 8.5±14.1 months). In independent PET‐ and autopsy‐analyses, we investigated age‐ and sex‐effects on Tau‐PET, Braak‐V/VI‐level tau neuropathology and tangle density. In PET‐to‐autopsy analyses, we assessed the correspondence of antemortem Tau‐PET with postmortem Braak‐V/VI neuropathology stratified for age (median‐split at 82.5y) and sex, as well as associations between Tau‐PET and tangle density according to age and sex. Result In PET‐analyses (age: 71.9±8.2, 54.3% male), older age and male sex were associated with a lower prevalence of Tau‐PET‐positivity (β=‐0.44, p <0.001 and β=‐0.43, p = 0.02 respectively) and lower Tau‐PET SUVr (β=‐0.34, p <0.001 and β=‐0.10, p = 0.007) (Figure 1A‐D). In autopsy‐analyses (age: 82.7±7.9, 54.7% male), older age and male sex were associated with a lower prevalence of Braak‐V/VI neuropathology (β=‐0.25, p <0.001 and β=‐0.40, p = 0.005). Among Braak‐V/VI autopsy cases ( n = 599), older age (β=‐0.38, p <0.001), but not male sex (β=‐0.05, p = 0.23), was associated with lower tangle density (Figure 1E‐H). In the PET‐to‐autopsy‐analyses (age: 82.0±8.8, 51.8% male), the specificity of Tau‐PET for detecting Braak‐V/VI tau was high across ages and sexes, but the sensitivity decreased with age and in males (Figure 2). Older and male participants with moderate‐to‐frequent CERAD showed both lower Tau‐PET and tangle density, and the lack of age/sex‐interactions indicate that the relationship between Tau‐PET and tangle density is consistent across ages and sexes (Figure 3). Conclusion Comprehensive and independent PET, autopsy, and PET‐to‐autopsy analyses demonstrate that the associations between older age and male sex with lower Tau‐PET uptake and prevalence are explained by lower tangle densities at autopsy. Tau‐PET closely reflects postmortem tangle density, which explains the lower sensitivity of Tau‐PET to detect Braak‐V/VI tau at lower densities frequently observed in older and male individuals.