Female-specific risk of Alzheimer's disease is associated with tau phosphorylation processes: A transcriptome-wide interaction analysis
Abstract
The levels of tau phosphorylation differ between sexes in Alzheimer's disease (AD). Transcriptome-wide associations of sex by disease interaction could indicate whether specific genes underlie sex differences in tau pathology; however, no such study has been reported yet. We report the first analysis of the effect of the interaction between disease status and sex on differential gene expression, meta-analyzing transcriptomic data from the 3 largest publicly available case-control studies (N = 785) in the brain to date. A total of 128 genes, significantly associated with sex-AD interactions, were enriched in phosphoproteins (false discovery rate (FDR) = 0.001). High and consistent associations were found for the overexpressions of NCL (FDR = 0.002), whose phosphorylated protein generates an epitope against neurofibrillary tangles and KIF2A (FDR = 0.005), a microtubule-associated motor protein gene. Transcriptome-wide interaction analyses suggest sex-modulated tau phosphorylation, at sites like Thr231, Ser199, or Ser202 that could increase the risk of women to AD and indicate sex-specific strategies for intervention and prevention.
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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 [22]
Limited findings from genome-wide and transcriptome-wide association studies in AD suggest that sample size is a critical consideration when examining sex interactions.
“Limited findings from genome‐wide 86 and transcriptome‐wide 18 , 22 association studies in AD also suggest that the sample size is a critical consideration when examining sex interactions.”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [22]
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- Authors
- Cáceres, A., & González, J. R.
- Affiliations
- Centro de Investigación Biomédica en Red (ES)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Cáceres, Alejandro
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 96
- Pages
- 104-108
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W3082405060
- Cited by
- 18
- References
- 20
- Citations by year
- 2025: 6 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 4
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
- Funders
- Spanish Ministry of Education
- Innovation and Universities
- National Agency for Research
- Fund for Regional Development (RTI2018-100789-B-I00)
- Catalan Department of Economy and Knowledge (SGR2017/801)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, sex differences, tau phosphorylation, transcriptome-wide association study, differential gene expression, brain transcriptomics, neurofibrillary tangles, NCL, KIF2A, microtubule motor proteins, neurodegeneration
- MeSH terms
- Nucleolin, Alzheimer Disease, Epitopes, Female, Humans, Male, Phosphoproteins, Phosphorylation, Risk, Sex Characteristics, Kinesins, RNA-Binding Proteins, Neurofibrillary Tangles, tau Proteins, Gene Expression Profiling, Genetic Association Studies, Transcriptome
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