Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease
Open accessAbstract
Despite recent advances in the understanding of clinical aspects of sex differences in Alzheimer's disease (AD), the underlying mechanisms, for instance, how sex modifies AD risk and why the female brain is more susceptible to AD, are not clear. The purpose of this study is to elucidate sex disparities in brain aging profiles focusing on 2 major areas-energy and amyloid metabolism-that are most significantly affected in preclinical development of AD. Total RNA isolated from hippocampal tissues of both female and male 129/C57BL/6 mice at ages of 6, 9, 12, or 15 months were comparatively analyzed by custom-designed Taqman low-density arrays for quantitative real-time polymerase chain reaction detection of a total of 182 genes involved in a broad spectrum of biological processes modulating energy production and amyloid homeostasis. Gene expression profiles revealed substantial differences in the trajectory of aging changes between female and male brains. In female brains, 44.2% of genes were significantly changed from 6 months to 9 months and two-thirds showed downregulation. In contrast, in male brains, only 5.4% of genes were significantly altered at this age transition. Subsequent changes in female brains were at a much smaller magnitude, including 10.9% from 9 months to 12 months and 6.1% from 12 months to 15 months. In male brains, most changes occurred from 12 months to 15 months and the majority were upregulated. Furthermore, gene network analysis revealed that clusterin appeared to serve as a link between the overall decreased bioenergetic metabolism and increased amyloid dyshomeostasis associated with the earliest transition in female brains. Together, results from this study indicate that: (1) female and male brains follow profoundly dissimilar trajectories as they age; (2) female brains undergo age-related changes much earlier than male brains; (3) early changes in female brains signal the onset of a hypometabolic phenotype at risk for AD. These findings provide a mechanistic rationale for female susceptibility to AD and suggest a potential window of opportunity for AD prevention and risk reduction in women.
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Sex differences in mitochondrial metabolism 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 [79]
The Results report sex differences in age-related expression of genes involved in energy metabolism, including mitochondrial electron transport and oxidative phosphorylation. But the Abstract and Discussion describe measurements in aging mice relevant to preclinical AD risk, not mitochondrial metabolism measured in people with AD; “in AD” extends the finding beyond the studied population and condition. (LLM, conf=0.85)
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- Authors
- Zhao, L., Mao, Z., Woody, S. K., & Brinton, R. D.
- Affiliations
- University of Southern California (US)
- University of Kansas (US)
- Corresponding author
- Zhao, Liqin
- ORCID
- Brinton, Roberta D.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 42
- Pages
- 69-79
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC5644989
- OpenAlex
- W2273721423
- Cited by
- 132
- References
- 55
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 12 · 2023: 11 · 2022: 6 · 2021: 15 · 2020: 19 · 2019: 20 · 2018: 14 · 2017: 7 · 2016: 8
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG026572)
- Alzheimer's Association (IIRG-10–172459)
- 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
- sex differences, Alzheimer's disease, brain aging, energy metabolism, hippocampus, gene expression profiling, clusterin, preclinical Alzheimer's disease, gene network analysis
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Disease Susceptibility, Energy Metabolism, Female, Hippocampus, Humans, Male, Mice, Inbred C57BL, Risk, Sex Characteristics, Gene Expression, Amyloid beta-Peptides
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