AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Early Hormone Replacement Therapy and Cognitive Outcomes in Postmenopausal Women
By Nouri A, Hoeft C, Rossi R et al.
Background: Hormone replacement therapy (HRT) initiated during the early postmenopausal period has been hypothesized to exert neurovascular protective effects through modulation of endothelial function and cerebrovascular health. However, the relationship between early HRT initiation and long-term dementia risk in postmenopausal women remains incompletely understood. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Postmenopausal women receiving estrogen-containing HRT with or without progesterone initiated within 10 years of menopause were compared with postmenopausal women without HRT exposure. The primary outcome was incident overall dementia, defined as vascular dementia, unspecified dementia, Alzheimer disease (AD), frontotemporal dementia, dementia with Lewy bodies, and dementia associated with other neurologic diseases. Secondary outcomes included cognitive impairment, stroke/transient ischemic attack (TIA), AD, vascular dementia, and venous thromboembolic events (VTE). Falsification endpoints included acute cholecystitis and nephrolithiasis. 1:1 propensity score matching (PSM) was performed using 53 variables, including demographic characteristics, medications, laboratory parameters, and comorbidities. Since ICD-based dementia diagnoses often reflect delayed recognition and coding rather than true disease onset, dementia outcomes were modeled as binary outcomes with estimation of risk ratios (RRs). Results: Before matching, 27,351 women receiving HRT and 229,671 women without HRT were identified. After PSM, 27,347 patients remained in each cohort. Following matching, women initiating HRT within 10 years of menopause had a lower risk of the primary endpoint of overall dementia compared with women not receiving HRT (4.0% vs 4.6%; RR 0.87, 95% CI 0.80-0.94; p=0.001). Among secondary endpoints, HRT was associated with lower risks of stroke/TIA (6.4% vs 7.5%; RR 0.86, 95% CI 0.81-0.91; p<0.001) and AD (1.4% vs 1.7%; RR 0.81, 95% CI 0.70-0.92; p=0.002). No significant difference was observed for vascular dementia (0.9% vs 1.0%; RR 0.86, 95% CI 0.73-1.02; p=0.086). In contrast, cognitive impairment was more frequent among women receiving HRT (5.4% vs 4.8%; RR 1.13, 95% CI 1.05-1.21; p=0.001). For safety outcomes, VTE was significantly increased in the HRT group (7.2% vs 5.2%; RR 1.38, 95% CI 1.29-1.47; p<0.001). Falsification endpoints, including acute cholecystitis and nephrolithiasis, were not significantly different between groups. Conclusions: Among postmenopausal women, initiation of HRT within 10 years of menopause was associated with lower cumulative risk of incident dementia but higher VTE risk. Further prospective studies are needed to clarify the impact of HRT timing, formulation, and duration on long-term cognitive outcomes.