A recent analysis of serum protein changes identified 16 proteins related to inflammatory, synaptic, metabolic, and Alzheimer’s disease processes whose levels change during the menopausal transition [1]. These changes were linked to cognitive health later in life.
The time for interventions
Menopause is mostly known as a stage that marks the end of female reproduction, but the effects of menopause go beyond the reproductive system and affect many organs and systems, with the impact on the brain being widely discussed and researched. For example, multiple studies have reported that women experience various cognitive difficulties during menopause, such as word-finding or attentional difficulties. A recent review estimated that such problems affect between 26 and 95% of menopausal women [2]. Additionally, different studies suggested that the aging of the hypothalamus plays a causal role in ovarian senescence and menopause induction [3]. These data suggest a strong connection between the brain and menopause, creating a window of opportunity during the menopausal transition for improving brain aging and affecting dementia risk.
“Menopause is a normal physiological process that every person who has ovaries who lives long enough will go through,” said Madeline Wood Alexander, a graduate student at the University of Toronto. “We don’t want it to be viewed as a bad thing, but as an opportunity to better understand and maybe modify the biology of brain aging in women.”
Kaitlin Casaletto, Ph.D., an associate professor at the UCSF Fein Memory and Aging Center and co-senior author of the study, added, “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.” “For women, menopause may be this especially powerful time to intervene.”
Menopause proteomic score
Although many studies suggest a connection between menopause and brain aging, human data remain scarce, limiting the ability to understand the underlying molecular pathways driving these processes.
The researchers of this study began by investigating blood biomarkers associated with spontaneous menopause in healthy midlife women (43-58 years old): 30 premenopausal, 26 perimenopausal, and 24 postmenopausal women, along with 36 age-matched men for comparison.
Comparing serum protein levels (proteomics) showed an increase in 16 proteins in postmenopausal women compared to premenopausal women after adjusting for age. These proteins were related to inflammatory, synaptic, metabolic, and Alzheimer’s disease processes, with inflammatory molecules predominant, consistent with previous studies showing increased systemic inflammation after menopause [4].
Because the cohort used to identify these protein changes was relatively small, they also analyzed data from almost 3,000 women in the UK Biobank. 13 of the 16 proteins identified as showing menopause-stage differences were measured in both cohorts; of those, 9 replicated across cohorts.
The observed changes in synaptic and Alzheimer’s disease blood markers align with previous animal studies showing synaptic plasticity and spine density disruptions [5, 6], along with increases in Aβ and tau positron emission tomography (PET) across menopause [7, 8].
Using those 16 proteins, the researchers created a proteomic score that holistically reflects major menopause-related changes with less data noise. Using this score, they showed that compared to premenopausal women, perimenopausal status was associated with an increase of 1.36 units in menopause scores, and postmenopausal status with a 3.25-unit increase. Importantly, the menopausal stage, rather than chronological age, drove the observed changes.
Hormonal changes and menopausal symptoms
One of the most important changes during menopause is hormonal changes, such as reductions in the ovarian hormones 17β-estradiol and progesterone along with increases in follicle-stimulating hormone (FSH).
In this study, the authors found a positive association between their menopause proteomic score and FSH levels, an inverse association between this score and estradiol levels, and no association with progesterone levels. At a more granular level, they reported that some inflammation-related protein levels were inversely associated with 17β-estradiol, which aligns with the role of estrogens in modulating immune responses [9], while other proteins related to inflammatory, synaptic, metabolic, and Alzheimer’s disease processes were positively associated with FSH.
The authors note that this aligns with previous studies showing that “FSH receptors are expressed abundantly in AD-vulnerable brain regions” and that data from animal models suggest FSH’s role in the development of Alzheimer’s disease, neuroinflammation, and cognitive deficits [10]. In their analysis, the identified proteins were clustered into two separate groups, which suggests that each hormone might be linked to different biological pathways.
Menopause is also widely known as a stage in life when women experience various vasomotor symptoms, such as night sweats or hot flashes, and some of those vasomotor symptoms have been associated with vascular inflammation [11, 12], cardiovascular risk, and Alzheimer’s disease-related brain changes [13]. In this study, the authors analyzed different cohorts for the association between menopausal score and vasomotor symptoms. The results were inconsistent across the cohorts, but some suggested a link between some vasomotor symptoms and menopausal score.
Predicting future cognitive health
Beyond many previously reported links between menopausal changes and brain health, these researchers tested how relevant changes in serum proteins are for later-life cognitive health. They analyzed data from four independent cohorts of older women and found a consistent association between higher (more postmenopausal) baseline menopause scores and worse cognitive health later in life and a higher risk for Alzheimer’s disease dementia, suggesting that changes in certain protein levels during menopause may remain relevant in later decades of life.
“We don’t think that menopause is directly causing dementia,” said Casaletto. “But it’s possible that we may be able to predict a woman’s risk for dementia decades later by the levels of these molecules around menopause.”
While all women will undergo menopause, only a fraction will develop dementia. Molecular signatures during the menopausal transition can provide the earliest signals of future risk of developing the disease.
“We’re identifying molecular shifts in blood, in midlife post-menopausal women, that are also predicting cognition later in life,” said co-senior author Rowan Saloner, Ph.D., assistant professor at the UCSF Fein Memory and Aging Center. “So, we think these molecules are really important markers of both menopause and cognitive aging.”
Literature
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