ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Single-cell landscape of sex-specific drivers of Alzheimer's disease.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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Who cites it
3 citing papers in PubMed.
- Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.Basic & clinical pharmacology & toxicology · 2026Review
- Review
- Single-cell landscape of sex-specific drivers of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors.
Funding
Abstract
introductionWe investigated sex-specific gene expression associations with the neuropathology and cognitive manifestation of Alzheimer's disease (AD) leveraging single-nucleus transcriptomic datasets including 2.84 million nuclei from the dorsolateral prefrontal cortex (DLPFC).
methodsWe delineated the full scope of sex-specific transcript associations, differential gene expression, signaling pathway, and cell-cell communication network changes in eight major DLPFC cell types.
resultsNine female-specific associations were identified and replicated, involving ADGRV1, OR3A3, IFI27L1, LYRM1, STAP2, TSTD2, PDYN, and TMEM50B. We observed the preponderance of protective female-specific associations in neurons. Sex-specific genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals that may contribute to female-specific risk of Aβ accumulation were also highlighted. DISCUSSION: Our study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline, with identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies. HIGHLIGHTS: Single-nucleus transcriptomic association analysis identified 2660 sex-specific associations involving 2110 genes with four AD endophenotypes. The majority of female-specific associations link to better endophenotype outcomes were from neurons. Nine female-specific associations were replicated, including ADGRV1 and OR3A3 with Aβ; IFI27L1, LYRM1, STAP2, and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive trajectory. Sex-specific effect genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals may play roles in female-specific risk for Aβ accumulation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.