Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer’s disease
Davina Biel, Marc Suárez‐Calvet, Anna Dewenter, Anna Steward, Sebastian Niclas Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier
Abstract
Abstract 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-tau 181 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-tau 181 . To determine effects of microglial activation on p-tau 181 , 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-tau 181 levels. Higher sTREM2 was associated with elevated p-tau 181 , with stronger associations in women. Similarly, ApoE4 was related to higher p-tau 181 levels and faster p-tau 181 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.