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-tau<sub>181</sub> 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<sub>181</sub>. To determine effects of microglial activation on p-tau<sub>181</sub>, 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<sub>181</sub> levels. Higher sTREM2 was associated with elevated p-tau<sub>181</sub>, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau<sub>181</sub> levels and faster p-tau<sub>181</sub> 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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-01-10
DOI
https://doi.org/10.1038/s44321-024-00190-3
Citations
8
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
9.31

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article

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

Annika Kreuzer, Amir Dehsarvi, Anna Dewenter, Anna Steward et al.
8 citations
EMBO Molecular Medicine
Alzheimer's disease research and treatments
9.31
article

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

Annika Kreuzer, Amir Dehsarvi, Anna Dewenter, Anna Steward, Matthias Brendel, Sebastian Niclas Roemer, Christian Haass, Zeyu Zhu, Michael Schöll, Lukas Frontzkowski, Nicolai Franzmeier, Davina Biel, Marc Suárez‐Calvet, Julia Pescoller
article en
8 citations

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<sub>181</sub> 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<sub>181</sub>. To determine effects of microglial activation on p-tau<sub>181</sub>, 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<sub>181</sub> levels. Higher sTREM2 was associated with elevated p-tau<sub>181</sub>, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau<sub>181</sub> levels and faster p-tau<sub>181</sub> 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.

EMBO Molecular MedicineVol. 17(2)
German Center for Neurodegenerative Diseases (DE), LMU Klinikum (DE), Pasqual Maragall Foundation (ES), Munich Cluster for Systems Neurology (DE), Barcelonaβeta Brain Research Center (ES), Hospital Del Mar (ES), Municipal Institute for Medical Research (ES), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES), Hospital del Mar Research Institute (ES), Ludwig-Maximilians-Universität München (DE), University of Gothenburg (SE)
Alzheimer's Disease Neuroimaging Initiative
Good health and well-being
Openalex Percentile: Top 2%
Alzheimer's disease research and treatments
9.31
DOIOpen Access PDFOpenAlex
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