Scientists map a blood protein fingerprint of menopause tied to brain health

A new study published in Nature Medicine reveals that menopause is associated with specific protein changes in the blood that may impact brain health. The research indicates that these molecular alterations are more closely linked to reproductive hormone levels than simply the passage of time. Older women with blood profiles showing more of these protein patterns tend to experience accelerated cognitive decline and a slightly increased risk of Alzheimer's disease.

Menopause marks the end of reproductive function in women, typically occurring around age 51, when ovarian hormone production declines sharply and menstrual periods cease. The drop in estrogen and progesterone levels is accompanied by a rise in follicle-stimulating hormone, a hormone produced by the pituitary gland. While symptoms like hot flashes, sleep disturbances, and memory issues often begin during midlife, Alzheimer's disease develops years earlier, coinciding with middle age.

Scientists have long suspected that hormonal and immune changes during menopause may make the brain more susceptible to neurodegeneration. A 2020 review suggested that the hormonal shifts during perimenopause, the period leading up to menopause, create a systemic inflammatory environment by disrupting immune regulation and cellular energy production in the brain.

Another 2023 study found that more frequent hot flashes during sleep were linked to lower levels of two amyloid proteins in the blood, suggesting a potential increase in brain amyloid deposition.

A 2025 study by the same research team published in Science Advances found that earlier menopause onset further strengthened the connection between brain aging markers and cognitive decline. To better understand the broader molecular changes underlying menopause, lead author Madeline Wood Alexander, along with co-senior authors Rowan Saloner and Kaitlin B. Casaletto, conducted the current study.

All three researchers are affiliated with the Ann S. Bowers Women’s Brain Health Initiative at the University of California and are based at the Sunnybrook Research Institute and the University of Toronto.

The study analyzed blood samples from 80 healthy women aged 43 to 58 and 36 age-matched men. Participants were classified based on menstrual regularity and hormone levels into premenopausal, perimenopausal, and postmenopausal groups. Blood samples were tested for six sex hormones and analyzed for 118 neurological, inflammatory, and metabolic proteins after fasting in the morning. Additional questionnaires assessed recent hot flashes, night sweats, vaginal dryness, and irritability.

After adjusting for age, the researchers found that 16 of the 118 proteins were elevated in postmenopausal women compared to premenopausal women. These proteins included eight inflammatory, four synaptic, two metabolic, and two Alzheimer's-related proteins: beta-secretase 1, an enzyme that produces amyloid, and phosphorylated tau-231, a protein involved in tau tangles associated with Alzheimer's disease.

Other standard Alzheimer's markers, such as phosphorylated tau-181 and amyloid-beta 42, did not show significant differences after adjusting for age.

To account for multiple comparisons and noise, the researchers combined the 16 elevated proteins into a single composite menopause proteomic score. This score increased stepwise across the hormonal transition, with perimenopausal women scoring 1.36 standard deviations higher and postmenopausal women scoring 3.25 standard deviations higher than premenopausal women in unadjusted comparisons.

While chronological age initially correlated with higher menopause proteomic scores, this link weakened and reversed direction after adjustment for menopause status.