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Updated: May 16, 2026
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Biomarker Identification for Gender Specificity of Alzheimer's Disease Based on the Glial Transcriptome Profiles
Published on: May 20, 2024
Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome
Zhiyi Wu1, Qinglong Tan1, Fei Xue1
1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Alzheimer'S Research & Therapy
|May 14, 2026
Summary
This study reveals sex-specific molecular differences in Alzheimer's disease (AD) brain cells. Females show greater vulnerability to AD pathology, while males have a higher genetic risk burden.
Area of Science:
- Neuroscience
- Genomics
- Cell Biology
Background:
- Alzheimer's disease (AD) disproportionately affects women, but the underlying molecular mechanisms of sex differences are unclear.
- Understanding these differences is crucial for developing targeted AD therapies.
- This research investigates sex-specific cellular and molecular changes in the AD brain.
Purpose of the Study:
- To investigate sex-specific differences in brain cells from individuals with and without Alzheimer's disease (AD).
- To identify sex-biased molecular patterns, including metabolic pathways, cell-cell communication, and senescence.
- To explore the distribution of AD genetic risk across different cellular states and sexes.
Main Methods:
- Analyzed over 3.3 million single-cell profiles from 603 samples across 10 cohorts.
- Applied non-negative matrix factorization to identify cell type-specific meta-programs (MPs) representing distinct cellular states (CSs).
- Examined sex differences in CSs focusing on metabolism, cell-cell communication, senescence, and disease relevance.
Main Results:
- Identified distinct metabolic pathways for inflammatory homeostasis in males and females.
- Found sex-biased ligand-receptor pairs mediating cell-cell communication linked to AD pathology.
- Revealed sex-biased enrichment of AD polygenic risk in specific neuronal and glial circuits.
- Observed distinct CS-specific signatures of cellular senescence in males and females with AD.
- Identified sex-biased meta-programs in oligodendrocytes (MP13) and excitatory neurons (MP1).
Conclusions:
- The study identified sex-biased meta-programs across major brain cell types in Alzheimer's disease.
- Females exhibit greater vulnerability to Aβ and tau pathology, whereas males carry a higher genetic risk burden.
- Cellular state heterogeneity plays a significant role in the sex differences observed in Alzheimer's disease.
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