Menopause marks the end of a woman’s menstrual periods, often accompanied by hot flashes and disrupted sleep.

Changes in blood proteins may also offer clues to brain health decades later.

Compared with women who hadn’t reached menopause, those past it had more of certain proteins tied to inflammation, brain cell signaling, and Alzheimer’s disease.

That difference followed hormone levels more closely than age.

The same protein pattern appeared again in older women. Those whose blood showed it more strongly tended to decline faster on memory and thinking tests.

In the largest group, they also had a modestly higher risk of Alzheimer’s dementia.

Menopause may be a window for spotting the earliest signs of brain aging, years before memory problems usually appear.

Menopause reaches beyond reproduction

The work was led by Madeline Wood Alexander at Sunnybrook Research Institute in Toronto, with Rowan Saloner and Kaitlin Casaletto at the University of California, San Francisco.

Because the findings come from blood samples and health records, they link these proteins to brain aging without showing that one causes the other.

“Menopause is not an isolated reproductive event,” said Emily Jacobs, a professor of psychological and brain sciences at UC Santa Barbara, whose lab runs the study that supplied the midlife volunteers.

“It is a whole-body biological transition. Now we can begin to see a molecular fingerprint of that transition in the blood and ask how it relates to brain health decades later.”

Protein differences across menopause stages

Menopause arrives around age 51 on average, more than two decades before dementia symptoms usually show up.

But the brain changes behind Alzheimer’s seem to start long before symptoms do, possibly around the same years as menopause.

The midlife part of the study included 80 healthy women aged 43 to 58. Thirty of them hadn’t reached menopause, 26 were in the transition often called perimenopause, and 24 had already passed through it.

In blood drawn after an eight-hour fast, the team measured about 120 proteins thought to be involved in brain aging. Sixteen of them were higher in women past menopause than in women who hadn’t reached it.

Eight of those 16 are involved in inflammation, four in the connections between nerve cells, and two in metabolism. The remaining two are tied to Alzheimer’s.

One is p-tau231, a form of tau, the protein that forms tangles inside brain cells in Alzheimer’s. The other is BACE1, an enzyme that helps make amyloid, the sticky protein in Alzheimer’s plaques.

The team also checked six standard Alzheimer’s blood markers. Once age was taken into account, p-tau231 was the only one that differed between women before and after menopause.

Hormones outweighed age

Next, the researchers combined the 16 proteins into a single score. It was lowest in women before menopause, higher in women in the transition, and highest in women past it.

Older women in the midlife group also had higher scores. That link disappeared once menopause stage was taken into account.

Thirty-six men of similar ages also gave blood, and in them the score didn’t rise with age at all.

Estradiol, the main form of estrogen, was about one-tenth as high in women past menopause as in women who hadn’t reached it.

Follicle-stimulating hormone, or FSH, was about nine times higher. The pituitary gland at the base of the brain releases FSH to signal the ovaries.

When estradiol, FSH, and progesterone were analyzed together, FSH was the only one still tied to the protein score.

Higher FSH was associated with higher levels of BACE1 and two proteins tied to nerve cell connections, while lower estradiol was associated with higher levels of four inflammation proteins.

The authors wrote that FSH receptors are common in brain regions that Alzheimer’s damages. In experiments on mice, FSH can trigger Alzheimer’s-like brain changes and thinking problems.

Results held in a larger group

To check the results, the team turned to the UK Biobank, which holds health data from about half a million volunteers in the United Kingdom.

They compared 1,407 women past menopause with 1,407 women who hadn’t reached it, all aged 45 to 60 and matched closely on age.

In those women, a different lab method measured 2,923 proteins, and about 44% of them differed between the two groups.

The larger analysis measured 13 of the original 16 proteins. Nine showed differences in the same direction as in the midlife volunteers.

The team also used aging clocks, computer models that estimate how old an organ looks from blood proteins tied to that organ.

On 11 of 13 organ measures, women past menopause looked biologically older than women of the same age who hadn’t reached it.

The arteries, brain, and intestine showed some of the largest differences.

Symptoms tracked inflammation

Among the midlife women in or past the transition, those who’d had night sweats in the previous two weeks had higher protein scores. They also had higher levels of four inflammation proteins.

Hot flashes, the sudden waves of heat many women feel around menopause, weren’t linked to the score in this group.

Women with vaginal dryness had lower scores, and the authors wrote that the meaning of that result is unclear.

Next came 89 older women, around 69 years old on average, from the Wisconsin Registry for Alzheimer’s Prevention, which enrolls many people with a parent who had Alzheimer’s.

Those who reported a history of hot flashes or sleep problems had higher protein scores years after menopause.

One inflammation protein, CCL2, was tied to heat symptoms in both groups: night sweats in the midlife women and hot flashes in the older ones.

CCL2 helps call immune cells to sites of inflammation, and the authors wrote that its link to heat symptoms may last into later life.

Thinking declined faster

The team then calculated the protein score for 11,925 older women in four separate groups, with average ages between about 61 and 72.

In a long-running Alzheimer’s study, 673 women around 71 years old were followed for about five years. Those with higher scores declined faster on memory and thinking tests.

The same was true in a smaller San Francisco study that followed 100 women for nearly six years.

The two groups started out very differently. More than half the women in the first study already had mild thinking problems or dementia at the start. Almost none in the San Francisco group did.

In the Wisconsin group, women with higher scores did worse on thinking tests taken at a single visit.

The UK Biobank group was the largest, with 11,059 women followed for nearly 16 years.

During that time, 219 of them developed Alzheimer’s dementia, and women with higher scores had a modestly higher risk of it. The scores weren’t linked to dementia of all types combined.

“Midlife is a critical window for both men and women where we can really set up the brain to be more resilient or more vulnerable to dementia in later life,” said Casaletto, one of the study’s senior authors.

“For women, menopause may be this especially powerful time to intervene.”

Limits of the findings

“The findings do not mean that menopause causes Alzheimer’s disease,” Casaletto said.

Most women don’t develop Alzheimer’s, she added, and it’s still unclear what small midlife rises in Alzheimer’s-linked proteins mean for any one person.

The authors described the link to Alzheimer’s dementia as relatively small.

The individual proteins most strongly associated with cognitive performance also varied across the groups of older women.

The authors wrote that the overall pattern may matter more than any one protein.

The midlife group was small and mostly White, and symptoms were self-reported. Proteins in the blood can also come from organs throughout the body, not only the brain.

Following women through menopause

“Women spend roughly one third of their lives after the menopause transition, yet we know remarkably little about the biology connecting menopause to later-life brain health,” Jacobs said.

Each midlife volunteer gave blood only once, so the study compared different women at different stages.

The authors wrote that confirming these shifts will mean following the same women from before menopause to years after it.

Those studies would track hormones, proteins, symptoms, and thinking along the way.

They could also separate the part of the change that comes from hormones from the part that comes with age.

The full study was published in the journal Nature Medicine.

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