A large, multi-cohort study has identified a distinctive pattern in blood proteins tied to inflammation, synaptic connections and brain ageing as women move through menopause. The researchers report that these molecular changes track more closely with reproductive hormone levels than with chronological age, and that older women with a stronger menopausal protein fingerprint show faster cognitive decline and a modestly higher risk of Alzheimer’s disease. The work, published in Nature Medicine, suggests blood-based markers could illuminate the biological pathways linking reproductive ageing with long‑term brain health.
The study’s lead author, Madeline Wood Alexander, a doctoral candidate in the Hurvitz Brain Sciences Program at Sunnybrook Research Institute and the Temerty Faculty of Medicine at the University of Toronto, collaborated with Rowan Saloner and Kaitlin B. Casaletto. Saloner and Casaletto are based at the Edward and Pearl Fein Memory and Aging Center in UCSF’s Weill Institute for Neurosciences, with all three researchers affiliated to the Ann S. Bowers Women’s Brain Health Initiative at the University of California.
In the discovery phase, the team analysed blood from 80 healthy women aged 43 to 58 and 36 age‑matched men from the UCSB Healthy Aging Study. By classifying the women as premenopausal, perimenopausal, or postmenopausal based on cycle regularity and hormone levels, they performed fasted morning serum tests for six sex hormones and an ultrasensitive assay measuring 118 neurological, inflammatory and metabolic proteins. Perimenopausal and postmenopausal participants reported recent hot flashes, night sweats, vaginal dryness and irritability.
Among the data, 16 of the 118 proteins were elevated in postmenopausal women after adjusting for age, spanning eight inflammatory proteins, four synaptic proteins, two metabolic proteins and two Alzheimer’s-related proteins, including beta-secretase 1 and phosphorylated tau-231. Other conventional Alzheimer’s markers, such as phosphorylated tau-181 and amyloid‑beta 42, did not show significant differences after age adjustment. To reduce noise, the researchers combined the 16 into a composite menopause proteomic score, which rose with the progression of menopausal status.
Chronological age initially correlated with higher menopause proteomic scores in women, but this link disappeared after adjusting for menopause stage, and the protein differences persisted even when the sample was narrowed to women aged 47 to 53. In the age‑matched male group, there was no age-related pattern, and men overall had higher composite scores than women once age was accounted for. Among the hormonal factors, while estradiol, FSH and progesterone were considered, only follicle‑stimulating hormone (FSH) remained a statistically significant predictor of the overall score. Regression analyses also showed that lower estradiol aligned with several inflammatory proteins, while higher FSH aligned with proteins across synaptic, metabolic, Alzheimer’s-related and inflammatory domains; network analysis suggested two distinct protein clusters.
In perimenopausal and postmenopausal women, reporting night sweats correlated with higher protein scores and elevated inflammatory markers, including CCL2/MCP-1. Vaginal dryness was unexpectedly linked with lower scores, while associations with hot flashes and irritability were not statistically significant.
To test broader applicability and reduce age confounding, the team turned to the UK Biobank. They matched 1,407 pre- or perimenopausal women with 1,407 postmenopausal peers of similar ages (45–60 years), excluding those with hysterectomy, oophorectomy or current hormone therapy. Across 2,923 plasma proteins, 1,300 differed by menopause status (1,146 elevated and 154 reduced post‑menopause), with nine of 13 overlapping discovery proteins replicated and the menopause proteomic score remaining higher in postmenopausal women.
The researchers then applied proteomic ageing clocks, which estimate an organ’s or cell type’s age from blood proteins relative to chronological age. Compared with younger counterparts, postmenopausal women showed older estimated ages in 11 of 13 organs and in 36 of 38 cell types, with the largest gaps in arteries, the intestines, the brain overall, and oligodendrocyte precursor cells.
The authors stressed that the observed brain‑related molecular elevations are not a diagnosis of Alzheimer’s disease. “All this evidence positions menopause as a key transition for the brain that may be relevant for women’s dementia risk, but very limited research has investigated the brain-relevant biology of the menopause transition in humans,” they explained. “This is a major gap because understanding what happens to the brain during menopause could help us identify which women may be at greater risk of neurodegenerative disease later in life, and ultimately, when and how we can best intervene to protect brain health. Our study aimed to start to address this gap by looking at blood levels of molecules related to brain health in a unique cohort of midlife women with hormone levels and detailed menopause staging.”
They framed their work as a proof of concept that brain‑related molecules can be detected in midlife women’s blood and show relevance to cognitive aging trajectories. “The key takeaways are (1) menopause is an important transition for brain health, involving not just changes to the reproductive system but shifts in immune, metabolic, vascular, and nervous systems (among others); and (2) we can use this window as an opportunity to understand women’s brain aging and dementia risk in its very early stages,” they said.
The study’s findings align with prior research suggesting brain changes around menopause, including a separate imaging study that reported postmenopausal women having reduced gray matter volume and slower reaction times, alongside higher anxiety and depression in some cases. Earlier cohort work has suggested higher lifetime estrogen exposure might be linked to better cognitive outcomes and larger brain volumes, potentially lowering dementia risk.
Caveats are acknowledged. The midlife analyses compared different individuals rather than following the same women through their final menstrual period, and the aging‑clock scores were derived from older blood samples in the aging cohorts, so they do not prove that midlife protein levels predict future decline. The discovery cohort’s predominantly White population and reliance on self‑reported symptoms are noted as limitations, with calls for more diverse, longitudinal research including objective symptom monitoring and brain imaging.
The authors also caution that the menopause proteomic score may reflect general ageing and inflammation biology beyond menopause and that the UK Biobank’s Alzheimer’s risk increase was modest. They emphasise that menopause does not cause dementia for the majority, and that the observed brain‑related molecular shifts may represent a compressed window of biological ageing in some women.
Looking ahead, the team said longitudinal studies tracking hormone changes, brain structure and function, and multi‑system health across the menopause are needed. They pointed to new multi‑site projects—the Longitudinal Menopause Project and the Women’s Brain Health Collaborative—as steps to map these trajectories more comprehensively.
The Nature Medicine paper, titled Blood proteomics of menopause map to brain aging and dementia risk, lists Madeline Wood Alexander, Jennifer S. Rabin, Michelle Caunca, Allesandra Iadipaolo and many colleagues among its authors, including Rowan Saloner and Kaitlin B. Casaletto.
