Blood proteins that shift at menopause tracked brain aging and dementia risk in 11,925 women

Menopause marks one of the biggest hormonal shifts of midlife, and researchers have long suspected it has consequences for the brain later on. How that might happen has been unclear. A study in Nature Medicine used large panels of blood proteins to look at the biology of menopause and how it relates to brain aging.

In 80 carefully staged women, menopause was linked to changes in proteins involved in inflammation, brain signaling, metabolism and Alzheimer’s disease. Those changes appeared again in 2,814 women. In 11,925 older women, higher scores on a menopause protein signature went with faster cognitive aging and higher dementia risk. The findings show associations, not cause and effect.

What menopause is and why the brain is involved

Menopause is dated from the final menstrual period, after a year without periods. The years leading up to it, the menopausal transition or perimenopause, bring changing cycles and falling levels of the ovarian hormones estrogen and progesterone. Researchers stage it with the STRAW+10 system, which reviewed the critical changes in hypothalamic-pituitary-ovarian function, the hormone signals between brain and ovaries, and set bleeding and hormone criteria for each stage, to be applied regardless of women’s age, ethnicity, body size, or lifestyle. The new study used this system to stage its first 80 women.

Many women notice memory lapses during the transition, and a large study measured them. The Study of Women’s Health Across the Nation followed 2,362 women for four years. Scores on processing speed and verbal memory normally improve with practice on repeat testing, but they stopped improving during perimenopause and recovered afterward. Its authors concluded that perimenopause was associated with a decrement in cognitive performance, and that the difficulties may be time-limited.

Earlier imaging work pointed to effects on the brain. A 2021 study in Scientific Reports found substantial differences in brain structure, connectivity, and energy metabolism across the stages before, during and after menopause. Those differences were tied to the hormonal aging of menopause rather than to age itself, and the brain biomarkers largely stabilized post-menopause.

How the menopause blood protein study worked

Proteomics means measuring hundreds or thousands of proteins in a blood sample at once. The researchers first studied 80 women aged 43 to 58 whose menopause stage had been carefully assigned with a standard staging system: before menopause, during the transition known as perimenopause, or after.

They then checked the findings in 2,814 women of similar ages, using a different protein test. Finally, they turned the menopause-linked proteins into a score and applied it in four independent groups of older women, with average ages from about 61 to 72 and 11,925 women in total. In those groups they looked at changes in thinking skills over time and at dementia risk.

What changed in the blood around menopause

In the first group, spontaneous menopause was linked to disrupted inflammatory, synaptic, metabolic and Alzheimer’s disease processes. Synaptic refers to synapses, the connections between nerve cells. These changes tracked more strongly with hormones than with age, which suggests they reflect the hormonal transition more than simply getting older.

The larger group replicated the observed proteomic shifts, meaning the same pattern of protein changes appeared again. It also pointed to a broader rise in inflammation and in processes that break down tissue, plus signs of accelerated organ and cell aging, including brain aging.

Estimating how fast organs are aging from blood proteins builds on earlier work. A 2023 study in Nature used blood proteins to estimate the biological age of 11 organs in 5,676 adults, and reported that accelerated brain and vascular aging predict the progression of Alzheimer’s disease. The same study found that nearly 20% of the population show strongly accelerated age in one organ, a sign of how unevenly the body ages.

How the menopause protein score related to dementia risk

Across the four groups of older women, higher menopause proteomic scores associated consistently with cognitive aging and dementia risk. Cognitive aging here means decline in thinking skills over time.

That makes the protein signature a candidate marker linking midlife hormonal change to later brain health. The authors suggest the molecular signatures of menopause may inform the selection of biomarkers or therapeutic targets for brain health in midlife women, meaning measurable signs to track and possible targets for future treatments.

What the menopause protein study cannot tell us

These are associations. The study cannot show that the protein changes of menopause cause cognitive decline or dementia, or that changing them would help. The older women’s protein scores were measured years after menopause, alongside everything else that had happened in between, from illnesses to medicines.

The first group was small, at 80 women, and the different groups were measured with different protein tests. The study focused on spontaneous menopause, and menopause brought on by surgery may differ. Blood proteins also come from many organs, so a change in the blood does not show directly what is happening inside the brain. It did not test hormone therapy or any other treatment, and it changes no guidance.

What this adds to menopause and brain health research

The study connects three things that are usually studied separately: the hormonal stages of menopause, blood proteins linked to inflammation and brain function, and later cognitive aging and dementia risk.

It offers a possible biological bridge between midlife and later brain health, which studies that follow women over many years would need to test.