Menopause age and hormone therapy use moderate PET tau and amyloid association: findings from the Wisconsin Registry for Alzheimer Prevention

Sex differences in tau deposition are apparent in clinically normal adults. Abnormal βamyloid (Aβ) may strengthen this association between sex and tau. Whether hormone therapy (HT) and menopause influence this higher tau retention in women and whether this is contingent upon Aβ burden is unclear. We examined differences in the cross-sectional association between Aβ and regional tau as a function of sex, HT-exposure and age-at-menopause. Data were collected from 292 cognitively unimpaired individuals from the Wisconsin Registry for Alzheimer’s Disease (mean age 67.43; 193 women [66%]; 106 APOEε4-carriers [37%]) who underwent dynamic0-70 [C-11] Pittsburgh Compound-B [PiB] and [F-18]-MK-6240 PET. The PiB distribution volume ratios (DVR) index reflects cortical Aβ burden. 90 [46.6%] women reported use of HT(past/current). Seven a priori tau regions previously demonstrating sex differences were selected (entorhinal cortex, amygdala, inferior temporal gyrus, middle and inferior temporooccipital gyri, superior parietal lobule and fusiform gyrus). Linear regressions (covarying age) examined the sex*PiB-DVR-index interaction for each tau-PET outcome and a preclinical Alzheimer’s cognitive composite (PACC). Similar models were examined in women alone for the same outcomes, investigating HT*PiB-DVR-index and age-at-menopause*PiB-DVR-index interactions. Women exhibited higher tau-PET with an increasing PiB-DVR-index relative to men (FDR;p’s:<0.002 in 5 tau regions. The HT*PiB-DVR-index analyses indicated that women with a higher PiB-DVR-index and self-reported HT use exhibited higher tau in five regions. The age-at-menopause* PiB-DVR-index interaction was significant in all regions and for the PACC, revealing subtle cognitive deficits in women with earlier age-at-menopause and a higher PiB-DVR index burden. Replicating previous studies, tau deposition was elevated in women compared with men. HT use and earlier age-at-menopause influenced the association between Aβ and tau and between Aβ and cognition. Cognitively unimpaired women with elevated Aβ burden may be vulnerable to hormonal changes related to hormone therapy and early menopause with implications for future anti-tauopathy clinical trials.