Timing of Menopausal Hormone Therapy May Impact Biomarkers of Alzheimer Disease

Menopausal hormone therapy (MHT) significantly accelerated the decline in amyloid beta 40 (Aβ40) levels among postmenopausal women and showed numerically greater effects on other Alzheimer disease (AD) biomarkers in women who started treatment within 6 of menopause, according to a secondary analysis of the Early vs Late Intervention Trial with Estradiol (ELITE) trial.

The findings were presented this week during The Menopause Society 2025 Annual Meeting in Orlando.

Researchers from the University of Southern California analyzed blood samples from 438 healthy postmenopausal women who participated in the ELITE trial. The study measured 6 AD biomarkers: Aβ40, Aβ42, Aβ42/Aβ40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau-181 (ptau181), at study baseline and 2.5 years following random assignment.

The original ELITE trial randomized 643 women stratified by menopausal stage, ie, early postmenopause (less than 6 years since menopause) or late postmenopause (10 years or more since menopause), to receive either 1 mg daily oral 17-β estradiol or placebo. Women with an intact uterus also received vaginal progesterone or placebo.

Findings Raise Concern

Across all participants, MHT significantly accelerated the decline in Aβ40 compared to placebo (P =.049), while effects on other biomarkers did not reach statistical significance. In early postmenopausal women, those treated with MHT showed numerically greater declines in Aβ42 and greater increases in the Aβ42/Aβ40 ratio compared to placebo, though these differences also fell short of statistical significance. GFAP levels declined in both treatment groups among early postmenopausal women, with slightly greater declines in the MHT group.

APOE-ε4 carriers at greater risk. Among women carrying the APOE-ε4 genetic variant, MHT produced a more pronounced decline in both Aβ40 and Aβ42 compared to placebo, although these differences also did not reach statistical significance.

Notably, MHT produced no effect on any biomarker in late postmenopausal women, a finding that aligns with the timing-dependent effects observed in the parent ELITE trial.

Roksana Karim, MD, PhD, and colleagues concluded that estradiol-containing MHT initiated in early postmenopause may influence trajectories of AD-related biomarkers, particularly measures of Aβ. The researchers noted that these findings partially support the critical window hypothesis—the concept that hormone therapy's effects depend on the timing of initiation relative to menopause—and underscore the need for larger studies to confirm potential neuroprotective effects of MHT during early postmenopause.

The study represents one of the first investigations into how MHT affects blood-based Alzheimer's biomarkers, which physicians increasingly use as tools for predicting Alzheimer's disease and related dementia.

Source: Yang Z, Rufino D, Yassine H, Hodis HN, Mack WJ, Karim R. Impact of menopausal hormone therapy on longitudinal changes in blood biomarkers of Alzheimer's disease by menopausal stage: a secondary analysis from the ELITE. Abstract presented at: The Menopause Society’s 2025 Annual Meeting; October 21-25, 2025; Orlando, FL. Accessed October 21, 2025.