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; Dehsarvi, Amir; Zhu, Zeyu; Pescoller, Julia; Frontzkowski, Lukas; Kreuzer, Annika; Haass, Christian; Schöll, Michael; Brendel, Matthias; Franzmeier, Nicolai

doi:http://dx.doi.org/10.1038/s44321-024-00190-3

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

Llicència

Citació

Biel D, Suárez-Calvet M, Dewenter A, Steward A, Roemer SN, Dehsarvi A, Zhu Z, Pescoller J, Frontzkowski L, Kreuzer A, Haass C, Schöll M, Brendel M, Franzmeier N. Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease. EMBO Mol Med. 2025 Feb;17(2):235-48. DOI: 10.1038/s44321-024-00190-3

Resum

In Alzheimer's disease (AD), Aß triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aß-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 Aß 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 Aß-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 Aß to p-tau axis, where women show higher Aß-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.