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

In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-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 Aβ 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 Aβ-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 Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women. Synopsis: This study examined whether sex, age, microglial activation or ApoE4 modulates the Aβ to p-tau axis, a critical event in the amyloid cascade that triggers the progression of Alzheimer's disease (AD) from amyloidosis towards tauopathy. Only sex but not age, sTREM2-related microglial activation or ApoE4 modulated the Aβ to p-tau axis. Higher sTREM2-related microglial activation and ApoE4 positivity were linked to elevated p-tau levels, with stronger associations in women than in men. Female sex is associated with a stronger Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation. This study examined whether sex, age, microglial activation or ApoE4 modulates the Aβ to p-tau axis, a critical event in the amyloid cascade that triggers the progression of Alzheimer's disease (AD) from amyloidosis towards tauopathy. [ABSTRACT FROM AUTHOR]