AUTHOR=Nerattini Matilde , Jett Steven , Andy Caroline , Carlton Caroline , Zarate Camila , Boneu Camila , Battista Michael , Pahlajani Silky , Loeb-Zeitlin Susan , Havryulik Yelena , Williams Schantel , Christos Paul , Fink Matthew , Brinton Roberta Diaz , Mosconi Lisa 

TITLE=Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer’s disease and dementia

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1260427

DOI=10.3389/fnagi.2023.1260427

ISSN=1663-4365

ABSTRACT=<sec><title>Introduction</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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, <italic>p</italic> &lt; 0.001], driven by estrogen-plus-progestogen therapy (EPT) [RR = 1.64, 95% C.I. 1.20–2.25, <italic>p</italic> = 0.002] and no significant effects of estrogen-only therapy (ET) [RR = 1.19, 95% C.I. 0.92–1.54, <italic>p</italic> = 0.18]. Conversely, observational studies indicate a reduced risk of AD [RR = 0.78, 95% C.I. 0.64–0.95, <italic>p</italic> = 0.013] and all-cause dementia [RR = .81, 95% C.I. 0.70–0.94, <italic>p</italic> = 0.007] with HT use, with protective effects noted with ET [RR = 0.86, 95% C.I. 0.77–0.95, <italic>p</italic> = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775–1.069, <italic>p</italic> = 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, <italic>p</italic> = 0.010] and non-significant reductions with midlife EPT [RR = 0.775, 95% C.I. 0.474–1.266, <italic>p</italic> = 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, <italic>p</italic> = 0.069; ET: RR = 1.066, 95% C.I. 0.996–1.140, <italic>p</italic> = 0.066].</p></sec><sec><title>Discussion</title><p>These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.</p></sec>