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

Biel, Davina; Suárez-Calvet, Marc; Dewenter, Anna; Steward, Anna; Roemer, Sebastian N; Dehsarvi, Amir; Zhu, Zeyu; Pescoller, Julia; Frontzkowski, Lukas; Kreuzer, Annika; Haass, Christian; Schöll, Michael; Brendel, Matthias; Franzmeier, Nicolai (2025): Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer’s disease. EMBO Molecular Medicine, 17 (2). pp. 235-248. ISSN 1757-4684

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.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine > Medical Center of the University of Munich > Institute for Stroke and Dementia Research (ISD)
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 390857198
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892