Estradiol reduction during perimenopause is associated with lower BDNF, elevated inflammation, hippocampal loss, and cognitive decline

The menopausal transition, defined by declining estradiol, disrupts neurotrophic and anti-inflammatory pathways, contributing to hippocampal and cognitive decline. In this longitudinal study, we examined 150 perimenopausal women and 80 premenopausal controls over 12 months, assessing estradiol levels, neurotrophic and inflammatory biomarkers, cognitive performance, and structural and functional hippocampal changes. This study assessed estradiol using LC-MS/MS, BDNF and cytokines (IL-6, TNF-α) via ELISA, memory and cognition with standardized neuropsychological tests, and hippocampal structure and function using 3-Tesla MRI, analyzed with FreeSurfer and SPM12. The results showed that over 12 months, perimenopausal women showed substantial declines in serum estradiol and BDNF levels, along with increases in the proinflammatory cytokines IL-6 and TNF-α, whereas premenopausal controls remained largely stable. These hormonal and biomarker changes were accompanied by impairments in hippocampal-dependent cognitive functions, including verbal, visuospatial, and working memory. MRI analyses revealed a 2.8% reduction in bilateral hippocampal volume and decreased functional activation during memory encoding. Correlation analyses indicated that estradiol decline was associated with reductions in BDNF, hippocampal volume, and hippocampal activation, as well as elevations in IL-6 and TNF-α. Mediation analyses demonstrated that BDNF and inflammatory markers (IL-6 and TNF-α) together accounted for 38% of the relationship between estradiol decline and memory impairment, suggesting partial mediation through neurotrophic and inflammatory pathways. Linear mixed-effects models revealed greater hippocampal volume loss and functional decline in perimenopausal women, with lower BDNF predicting reduced hippocampal activation and higher IL-6 linked to hippocampal atrophy. In short, the decline in estradiol during perimenopause may drive reductions in neurotrophic support and increase inflammation, contributing to hippocampal structural and functional changes and memory impairments.