Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease

In Alzheimer's disease (AD), A beta triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of A beta-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar A beta and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau181. To determine effects of microglial activation on p-tau181, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher A beta-related p-tau181 levels. Higher sTREM2 was associated with elevated p-tau181, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau181 levels and faster p-tau181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the A beta to p-tau axis, where women show higher A beta-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.