Summary

A Nature Medicine study identified menopause-related blood protein patterns associated with hormonal changes, brain aging and less favourable cognitive outcomes later in life. The observational findings provide a research framework for studying how the menopause transition may intersect with dementia risk.

A study in Nature Medicine has identified a blood-based molecular signature of menopause that was associated with brain aging, cognitive decline and later Alzheimer’s disease dementia risk. The researchers first analysed 80 rigorously staged women aged 43–58, then replicated the main protein shifts in 2,814 age-matched women and examined their relationship with cognitive outcomes in four older cohorts totalling 11,925 women.

The study was observational: it measured menopause-related proteins and their associations with later outcomes rather than testing a treatment or screening programme. Its central finding is that the menopause transition is accompanied by coordinated changes in inflammatory, metabolic, synaptic and Alzheimer’s disease-related biology that may be useful for future brain-health research.

Contents

A blood-based menopause score

The discovery cohort included 30 premenopausal, 26 perimenopausal and 24 postmenopausal women, with menopause stages assigned using the STRAW+10 criteria. The researchers measured 118 proteins in serum using NULISAseq, an ultrasensitive assay that uses DNA barcodes and next-generation sequencing to quantify proteins.

After adjusting for age, 16 proteins were elevated in postmenopausal compared with premenopausal women. They included inflammatory proteins such as CCL13, IL-12p70, CXCL1 and CCL2; synaptic and neuronal proteins including CNTN2, ACHE, SNAP25 and BDNF; metabolic targets including IGFBP7 and IGF1R; and proteins related to Alzheimer’s biology, including BACE1 and p-tau231.

The team combined these 16 measurements into a menopause proteomic score using principal-component analysis. The first component explained 28.7% of the variation in the selected proteins, and the score rose stepwise from premenopause to perimenopause and postmenopause.

The protein pattern tracked more strongly with hormone levels than with chronological age. Higher scores were associated with lower 17β-estradiol and higher follicle-stimulating hormone, or FSH. When the hormones were modelled together, FSH was the only one that remained significantly associated with the score. Inflammatory proteins were especially elevated in some women with vasomotor symptoms: night sweats in the midlife cohort were associated with higher levels of CCL13, CXCL1, CCL26 and CCL2.

Replication across cohorts and platforms

The researchers tested the findings in 2,814 women aged 45–60 from the UK Biobank, using plasma Olink measurements and matching pre/perimenopausal and postmenopausal participants on age. Of 2,923 proteins measured, 1,300 differed by menopause stage after false-discovery-rate correction: 1,146 were higher and 154 lower in postmenopausal women.

Nine of the 13 menopause-related proteins measured on both platforms showed clear replication. The larger analysis also found increases in pathways involving cytokine signalling, complement activation and extracellular-matrix breakdown. Proteomic estimates of biological age were less favourable after menopause for 11 of 13 organ measures and 36 of 38 cell-age measures. Brain and artery age were among the organ measures associated with menopause stage, while oligodendrocyte precursor-cell aging was among the highlighted cellular measures.

This cross-platform replication supports the presence of a broader menopause-associated biological pattern rather than a finding limited to one small group or one assay. However, the composite score was created from a targeted central-nervous-system panel and represents only part of the wider protein changes detected in the UK Biobank analysis.

The study next examined whether higher menopause proteomic scores were associated with cognitive outcomes years after the menopause transition. In the Alzheimer’s Disease Neuroimaging Initiative, 673 women were followed for an average of about five years; higher baseline scores were associated with a steeper rate of cognitive change, with a coefficient of β = −0.30 (95% confidence interval −0.42 to −0.18).

A similar association was observed in the UCSF Brain Aging Network for Cognitive Health, which included 100 women: β = −0.03 (95% confidence interval −0.05 to −0.002). In the Wisconsin Registry for Alzheimer’s Prevention, a cross-sectional cohort of 93 women, higher scores were associated with lower global cognitive performance, β = −0.27 (95% confidence interval −0.51 to −0.04).

In the UK Biobank analysis of 11,059 women without known dementia at baseline, participants were followed for a mean of 15.7 years. Higher menopause scores were associated with greater risk of incident Alzheimer’s disease dementia, with a hazard ratio of 1.15 (95% confidence interval 1.01–1.31; 219 events). The study did not find statistically significant associations with frontotemporal, vascular or all-cause dementia in the corresponding analyses.

A research framework for midlife brain health

The findings place menopause in a potentially important midlife window for studying brain aging. The authors propose that endocrine changes, particularly falling estradiol and rising FSH, may coincide with inflammatory, synaptic and metabolic shifts that remain relevant to cognitive health later in life. The results do not imply that menopause leads inevitably to dementia; most women do not develop dementia.

Several features keep the findings at the research stage. The discovery cohort was small and cross-sectional, menopause symptoms were self-reported, and proteins measured in blood can come from multiple tissues. Menopause status in the UK Biobank was assessed less precisely than in the rigorously staged discovery cohort. The clinical meaning of the modest midlife increases in p-tau231 and BACE1 is also not established by this study.

Longitudinal studies following the same women through hormone changes, symptoms, blood proteins and cognitive or brain measures will be needed to determine how these signals develop over time. For now, the menopause proteomic score is a research measure that may help identify biological pathways and candidate biomarkers for future studies of brain health.

Sources