BLOOD protein changes associated with menopause may offer insights into brain ageing and later cognitive health, according to research involving almost 15,000 women across multiple cohorts.
Researchers identified menopause-related molecular changes affecting inflammatory, metabolic, and neurological pathways. These changes were more strongly associated with hormonal shifts than chronological age, while higher menopause-related protein scores were linked to poorer cognitive outcomes in later life.
Researchers initially analysed blood samples from 80 women aged between 43 and 58 years, comprising of 30 premenopausal, 26 perimenopausal, and 24 postmenopausal participants.
Using an ultrasensitive protein analysis technique, they identified 16 proteins that were elevated in postmenopausal women compared with premenopausal women.
These proteins were associated with immune responses, synaptic function, metabolism, and biological processes implicated in Alzheimer’s disease.
The researchers combined the findings into a menopause-related proteomic score, which increased progressively across the menopause transition.
Higher scores were associated with lower oestradiol concentrations and higher follicle-stimulating hormone levels. When hormonal measures and age were examined together, hormone levels showed a stronger relationship with the protein changes than chronological age.
The findings were subsequently examined in 2,814 age-matched women from UK Biobank.
Of the 2,923 proteins assessed, 1,300 differed significantly according to menopausal status, with most showing higher concentrations after menopause.
The researchers also identified molecular patterns associated with accelerated biological ageing across several organs and cell types, including the brain.
Among 2,340 women assessed using protein-based ageing measures, postmenopausal participants had less favourable age estimates for 11 of 13 organs and 36 of 38 cell types compared with premenopausal or perimenopausal women of similar ages.
These findings suggest that the menopause transition may involve broader biological changes extending beyond the reproductive system.
The researchers then investigated the relationship between menopause-related protein signatures and cognitive health in four independent cohorts of older women, involving 11,925 participants.
Higher proteomic scores were consistently associated with less favourable cognitive outcomes, including faster cognitive decline in two longitudinal cohorts.
In a UK Biobank analysis involving 11,059 women followed for approximately 15.7 years, higher menopause-related protein scores were associated with a 15% increased hazard of Alzheimer’s disease dementia.
However, significant associations were not observed for all-cause, vascular, or frontotemporal dementia.
The study was observational and does not establish that menopause-related protein changes cause dementia. The researchers also emphasise that most women do not develop dementia following menopause.
Nevertheless, the findings suggest that the menopause transition could provide an important opportunity to investigate molecular markers associated with later brain health and identify potential therapeutic targets.
Reference
Wood Alexander M. et al. Blood proteomics of menopause map to brain aging and dementia risk. Nat Med. 2026. doi:10.1038/s41591-026-04648-4.
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