Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women With Alzheimer’s Disease
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Abstract
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (APOE ε4) AD risk compared to males, molecular signatures underlying these differences remain elusive. Methods: We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls in seven independent datasets. Sex-specific gene expression patterns were investigated through use of gene-based, pathway-based and network-based approaches. The ability of a sex-specific AD gene expression signature to distinguish Alzheimer’s disease from healthy controls was assessed using a linear support vector machine model. Cell type deconvolution from whole blood gene expression data was performed to identify differentially regulated cells in males and females with AD. Results: Strikingly gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. In females, network-based analysis revealed a coordinated program of gene expression involving several zinc finger nuclease genes related to Herpes simplex viral infection whose expression was modulated by the presence of the APOE ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD patients. Cell type deconvolution identified an increase in neutrophils and naïve B cells and a decrease in M2 macrophages, memory B cells, and CD8+ T cells in AD samples compared to controls in females. Interestingly, among males with AD, no significant differences in immune cell proportions compared to controls were observed. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features produced an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. Conclusion: These results help identify sex and APOE ε4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.
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Relative to healthy control females, females with AD possess a higher prevalence of less phagocytic pro-inflammatory macrophages.
“Further studies have also shown that relative to healthy control females, females with AD possess a higher prevalence of less phagocytic pro-inflammatory macrophages [28].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [28]
The Results section on cell-type deconvolution (page unavailable) reports fewer M2 macrophages in blood samples from females with AD than in female controls. It does not report a higher prevalence of pro-inflammatory macrophages or measure whether macrophages were less phagocytic. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe diminishing B cells in AD is more pronounced in females.
“our findings revealed that the diminishing B cells in AD is more pronounced in females”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [71]
The Results section on cell-type deconvolution reports decreased memory B cells in females with AD and no significant immune-cell proportion differences in males. But it also reports increased naïve B cells in females with AD, so the source does not support a general decrease in B cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMolecular differences in females are more predictive of AD than molecular differences in males.
“Our results are consistent with another recent study on sex-specific analysis of gene expression changes in AD, which found gene expression-based prediction models also performed better in females than in males [71], suggesting molecular differences in females are more predicative of AD.”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [71]
Female-specific pathways are enriched in immune response, insulin signaling, and tau phosphorylation.
“Female‐specific pathways were found to be enriched in immune response, 17 , 18 , 19 insulin signaling, 20 , 21 and tau phosphorylation, 22”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [17]
Transcriptome-wide sex differences in AD have been characterized in multiple studies.
“While transcriptome‐wide sex differences in AD have been characterized in multiple studies, 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 proteome‐wide sex differences in AD remain underexplored.”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [17]
Sex differences in immune response have been reported in AD.
“Although sex differences in immune response 17 , 18 , 19 and mitochondrial metabolism 79 have been reported in AD, other molecular processes identified here remain understudied.”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [17]
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Self-citationDistinct sex-specific DNA methylation differences in Alzheimer’s disease
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“Our results are consistent with another recent study on sex-specific analysis of gene expression changes in AD, which found gene expressionbased prediction models also performed better in females than in males [71], suggesting molecular differences in females are more predicative of AD.”
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Functional variants identify sex-specific genes and pathways in Alzheimer’s Disease
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Relationship between sex biases in gene expression and sex biases in autism and Alzheimer’s disease
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Do microbes play a role in Alzheimer's disease?
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Sex‐specific biomarkers in Alzheimer's disease progression: Framingham Heart Study
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The characteristics of brain atrophy prior to the onset of Alzheimer’s disease: a longitudinal study
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A case for seeking sex-specific treatments in Alzheimer’s disease
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Transcriptomic predictors of rapid progression from mild cognitive impairment to Alzheimer's disease
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Self-citationSex-related differences in genetically determined Alzheimer’s disease
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Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes
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“Further studies have also shown that relative to healthy control females, females with AD possess a higher prevalence of less phagocytic pro-inflammatory macrophages [28].”
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The brief resilience scale: a genome-wide association study in the UK Biobank
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Biological underpinnings of sex differences in neurological disorders
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Sex, ApoE4 and Alzheimer’s disease: rethinking drug discovery in the era of precision medicine
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Self-citationBlood-based sex-differential DNA methylation in Alzheimer’s disease
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Additional file 2 of Distinct sex-specific DNA methylation differences in Alzheimer’s disease
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Additional file 1 of Distinct sex-specific DNA methylation differences in Alzheimer’s disease
C. Silva, T., Zhang, W., Young, J. I., Gomez, L., Schmidt, M. A., Varma, A., Chen, X. S., Martin, E. R., & Wang, L. (2022) · Figshare · doi:10.6084/m9.figshare.21129953
Fass, S. B., Mulvey, B., Chase, R., Yang, W., Selmanovic, D., Chaturvedi, S. M., Tycksen, E., Weiss, L. A., & Dougherty, J. D. (2024) · Figshare · doi:10.6084/m9.figshare.26730721
Fass, S. B., Mulvey, B., Chase, R., Yang, W., Selmanovic, D., Chaturvedi, S. M., Tycksen, E., Weiss, L. A., & Dougherty, J. D. (2024) · Figshare · doi:10.6084/m9.figshare.26730727
Fass, S. B., Mulvey, B., Chase, R., Yang, W., Selmanovic, D., Chaturvedi, S. M., Tycksen, E., Weiss, L. A., & Dougherty, J. D. (2024) · Figshare · doi:10.6084/m9.figshare.26730712
Sex-dependent grey matter atrophy in Alzheimer’s disease progression
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- Authors
- Paranjpe, M. D., Belonwu, S., Wang, J. K., Oskotsky, T., Gupta, A., Taubes, A., Zalocusky, K. A., Paranjpe, I., Glicksberg, B. S., Huang, Y., & Sirota, M.
- Affiliations
- Harvard University (US)
- University of California, San Francisco (US)
- Gladstone Institutes (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Sirota, Marina
- ORCID
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2021-09-30
- Volume
- 13
- Pages
- 735611-735611
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC8515049
- OpenAlex
- W3203119495
- Cited by
- 49
- References
- 77
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 15 · 2023: 8 · 2022: 7 · 2021: 4 · 2020: 1
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH-12, W81XWH1220012, AG024904)
- Foundation for the National Institutes of Health (W81XWH-12-2-0012, R01AG060393, U01AG024904, Grant U01 AG024904, AG024904)
- Alzheimer's Association (U01 AG024904, W81XWH-12-2-0012)
- Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (W81XWH-12-2-0012, U01 AG024904)
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, Grant U01 AG024904, AG024904)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
- National Institute on Aging (U01-AG-024904, W81XWH-12-2–0012, AG 024904, 1R0AG057683, R01AG060393, R01AG057683)
- National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, sex differences, APOE ε4, immune dysregulation, herpes simplex virus, cell type deconvolution, whole blood transcriptomics, brain transcriptomics, neutrophils, M2 macrophages, CD8+ T cells, naive B cells, Alzheimer's disease classification, biomarkers
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