Evidence map›Paper›PMID 42135783›Full record

ArticleAlzheimer's research & therapy2026

Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome.

Zhiyi Wu, Qinglong Tan, Fei Xue, Zhuotong Jiang, Hongyu Zhao, Yuting Zhang, Yiming Liu, Yu Zhang, Danli Ding, Hongping Chen and 3 more

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Article in Alzheimer's research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

13 authors.

Zhiyi Wu *College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Qinglong Tan *College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Fei XueCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Zhuotong JiangCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Hongyu ZhaoCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Yuting ZhangCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Yiming LiuCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Yu ZhangCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Danli DingCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Hongping ChenDepartment of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
Yingqi XuCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China. xuyingqi1987@163.com.
Feng LiCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China. lifeng@hrbmu.edu.cn.
Chunlong ZhangCollege of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China. zhangchunlong@hrbmu.edu.cn.

Funding

Natural Science Foundation of Heilongjiang Province LH2023C062
6 · The paper itself

Abstract

backgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder that disproportionately affects women. However, the molecular mechanisms underlying sex differences in AD remain poorly understood.

methodsIn this study, we curated 3,302,741 single-nucleus or single-cell profiles from 603 samples (296 female and 307 male samples; 339 AD and 264 normal) across 10 cohorts to investigate sex-specific differences in the brain of individuals with and without AD. Focusing on six major cell types, we applied non-negative matrix factorization at the sample level to identify cell type -specific meta-programs (MPs). These MPs consist of mutually exclusive and functionally orthogonal gene set, representing different functional states of brain cells. Using these MPs, we characterized cellular states (CSs) across four sex-disease groups. We then examined sex differences in both AD and normal brains at the level of cellular states, with emphasis on metabolism, cell-cell communication, senescence, and disease relevance.

resultsMetabolic profiling revealed that inflammatory homeostasis is maintained through distinct metabolic pathways in males and females. Cell-cell communication analysis showed that the same cellular state interaction network is linked to AD pathology through sex-biased ligand-receptor pairs. Disease association analyses further indicated that polygenic risk for AD is not uniformly distributed across cell states, but instead shows sex-biased enrichment in specific neuronal and glial circuits. Senescence analysis suggested that males and females exhibit distinct CS-specific signatures of cellular senescence in AD. Additionally, we identified oligodendrocytes MP13 and excitatory neuron MP1 as sex-biased meta-programs.

conclusionsOverall, our study identified sex-biased MPs across six major cell types and revealed that females displayed greater vulnerability to Aβ and tau pathology, while males carry a higher genetic risk burdens. These findings highlight cellular state heterogeneity underlying sex differences in AD.

Indexed as

Alzheimer DiseaseBrainSex CharacteristicsTranscriptomeFemaleHumansMaleSingle-Cell AnalysisSingle-Cell Gene Expression AnalysisAlzheimer's diseaseCellular statesSex differenceSingle-cell RNA sequencingTranscriptome meta-programs

Identifiers

PMID42135783
PMCPMC13343642

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