Biel, DavinaSuárez-Calvet, MarcDewenter, AnnaSteward, AnnaRoemer, SebastianDehsarvi, AmirZhu, ZeyuPescoller, JuliaFrontzkowski, LukasKreuzer, AnnikaHaass, ChristianSchöll, MichaelBrendel, MatthiasFranzmeier, Nicolai2025-10-302025-10-302025Biel 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/s44321-024-00190-31757-4676http://hdl.handle.net/10230/71724In 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.application/pdfeng© 2025 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.info:eu-repo/semantics/article2025-10-30http://dx.doi.org/10.1038/s44321-024-00190-3Alzheimer's DiseaseMicrogliaSex Differencesp-tausTREM2info:eu-repo/semantics/openAccess