Alzheimer's Imaging Consortium

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.

Tau-PET-analyses included amyloid-positive participants with MCI or dementia who underwent [¹⁸F]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.

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).

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.