This research used blood proteomics to characterize molecular changes that occur with spontaneous menopause and to evaluate links between those changes and later brain aging and dementia risk. In a discovery set of rigorously staged midlife women (n = 80, ages 43–58 years) profiled with serum NULISAseq, menopause was marked by dysregulation in inflammatory, synaptic, metabolic and Alzheimer’s disease–related biological processes. These proteomic shifts aligned more closely with hormonal state than with chronological age. Validation in an independent, age-matched sample (n = 2,814) using plasma Olink proteomics reproduced the findings and revealed broader upregulation of inflammatory and catabolic pathways plus signatures of accelerated organ and cell aging, including brain aging. Across four additional cohorts of older women (average age range reported 60.7–72.1 years; total n = 11,925), higher menopause proteomic scores were consistently associated with cognitive aging and greater dementia risk. The authors suggest these molecular signatures may inform selection of biomarkers or therapeutic targets for midlife brain health in women.
The discovery analysis comprised n = 80 women aged 43–58 years who were staged according to STRAW+10 criteria as pre-, peri- or postmenopausal and profiled using serum NULISAseq proteomics. The authors performed a validation analysis in an age-matched set of pre-/peri- and postmenopausal women (n = 2,814) using plasma Olink proteomics. Further testing of the derived menopause proteomic scores was performed across four independent cohorts of older women (average ages reported between 60.7 and 72.1 years) comprising a total of n = 11,925 participants. The source text does not provide cohort names, follow-up intervals, or detailed demographic breakdowns for each cohort in the excerpt provided.
In the discovery set, spontaneous menopause corresponded with dysregulation of multiple biological processes as detected in blood. Key pathways highlighted included inflammatory processes, synaptic biology, metabolic pathways and processes related to Alzheimer’s disease. The authors note that these menopause-associated proteomic changes tracked more strongly with hormone measures than with chronological age, suggesting endocrine shifts around menopause are a principal driver of the observed molecular alterations.
Validation analyses in a substantially larger, age-matched cohort (n = 2,814) using a different proteomic platform replicated the primary proteomic shifts. In this cohort the menopause-associated profile extended to broader upregulation of inflammatory and catabolic pathways and produced signals interpreted as accelerated organ- and cell-level aging, including signatures consistent with brain aging. These replication results support robustness of the core finding across serum/plasma matrices and proteomic platforms. The source article excerpt does not report the specific proteins, numerical effect sizes, or statistical parameters in these analyses.
The authors applied derived menopause proteomic scores to four independent cohorts of older women (total n = 11,925; mean ages reported 60.7–72.1 years). Across these samples, higher menopause-related proteomic scores were consistently associated with measures of cognitive aging and with increased risk of dementia. This cross-cohort consistency suggests that blood proteomic signatures of the menopause transition may have value as predictors or markers of later-life cognitive trajectories in women. Precise cognitive outcomes, hazard ratios or adjustments for potential confounders are not detailed in the provided text.
The molecular signatures identified around menopause could help prioritize candidate biomarkers for monitoring midlife brain health in women and might highlight therapeutic targets to mitigate downstream risk for cognitive decline and dementia. Because the proteomic changes were more strongly linked to hormonal status than to age per se, the findings underscore a potential mechanistic role for endocrine changes of menopause in promoting inflammatory, metabolic and synaptic alterations relevant to neurodegeneration.
The summary above is restricted to information reported in the provided source excerpt. Important methodological and result details were not included in that excerpt and therefore are not claimed here: for example, the exact lists of altered proteins, full statistical results, cohort names and recruitment methods, covariates used in models, duration of clinical follow-up, and whether analyses adjusted for factors such as cardiovascular risk or hormone therapy were not reported in the text available for this rewrite. Readers should consult the full published article for complete methods, numerical results and cohort descriptions.