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Cited by 164Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchSex and Gender in Healthcare

Sex Differences in Alzheimer’s Disease: Insights From the Multiomics Landscape

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Guo, Lei, Zhong, Margaret B., Zhang, Larry, Zhang, Bin, Cai, Dongming·2022·Biological Psychiatry
DOI 10.1016/j.biopsych.2021.02.968PMC PMC8996342
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Abstract

Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.

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  • Alzheimer's disease affects women disproportionately.

    “It affects women disproportionally as manifested in many aspects such as disease prevalence, clinical presentation, neuroimaging studies and treatment responsiveness from clinical trials [1].”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [1]

    The Abstract says approximately two-thirds of patients with Alzheimer’s disease are female and reports sex differences in clinical and neuroimaging studies. It does not establish disproportionate treatment responsiveness in women from clinical trials; instead, it says sex-specific trial analyses were performed only occasionally and that sex should be considered when assessing treatment responses. (LLM, conf=0.86)

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Sorted by citations

Authors
Guo, L., Zhong, M. B., Zhang, L., Zhang, B., & Cai, D.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Columbia University (US)
  • James J. Peters VA Medical Center (US)
Corresponding author
  • Zhang, Bin
  • Cai, Dongming
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2022-01
Volume
91
Issue
1
Pages
61-71
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2021.02.968
PMC
PMC8996342
OpenAlex
W3134003013
Cited by
164
References
15
Citations by year
2026: 18 · 2025: 33 · 2024: 51 · 2023: 38 · 2022: 16 · 2021: 8
FWCI
3.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (R56AG058655, RF1AG054014, RF1AG057440, 1R01AG048923, RO1AG057907, RO1AG068030, UO1AG046170, UO1AG052411)
  • U.S. Department of Veterans Affairs
  • Rehabilitation Research and Development Service (I01RX002290)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
Keywords
Alzheimer's disease, sex differences, sex chromosomes, sex hormones, APOE ε4, neuroinflammation, energy metabolism, brain cell types, single-cell transcriptomics, cell type deconvolution, multi-omics
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Brain, Female, Genotype, Humans, Male, Sex Characteristics

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