Introduction: Despite a large preclinical literature demonstrating neuroprotective effects of estrogen, use of menopausal hormone therapy (HT) for Alzheimer’s disease (AD) risk reduction has been controversial. Herein, we conducted a systematic review and meta-analysis of HT effects on AD and dementia risk.

Methods: Our systematic search yielded 6 RCT reports (21,065 treated and 20,997 placebo participants) and 45 observational reports (768,866 patient cases and 5.5 million controls). We used fixed and random effect meta-analysis to derive pooled relative risk (RR) and 95% confidence intervals (C.I.) from these studies.

Results: Randomized controlled trials conducted in postmenopausal women ages 65 and older show an increased risk of dementia with HT use compared with placebo [RR = 1.38, 95% C.I. 1.16–1.64, p < 0.001], driven by estrogen-plus-progestogen therapy (EPT) [RR = 1.64, 95% C.I. 1.20–2.25, p = 0.002] and no significant effects of estrogen-only therapy (ET) [RR = 1.19, 95% C.I. 0.92–1.54, p = 0.18]. Conversely, observational studies indicate a reduced risk of AD [RR = 0.78, 95% C.I. 0.64–0.95, p = 0.013] and all-cause dementia [RR = .81, 95% C.I. 0.70–0.94, p = 0.007] with HT use, with protective effects noted with ET [RR = 0.86, 95% C.I. 0.77–0.95, p = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775–1.069, p = 0.251]. Stratified analysis of pooled estimates indicates a 32% reduced risk of dementia with midlife ET [RR = 0.685, 95% C.I. 0.513–0.915, p = 0.010] and non-significant reductions with midlife EPT [RR = 0.775, 95% C.I. 0.474–1.266, p = 0.309]. Late-life HT use was associated with increased risk, albeit not significant [EPT: RR = 1.323, 95% C.I. 0.979–1.789, p = 0.069; ET: RR = 1.066, 95% C.I. 0.996–1.140, p = 0.066].

Discussion: These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.