Association between duration, initiation time, routes, and formulations of menopausal hormone therapy use and Alzheimer disease in women: A systematic review and meta-analysis.

The purpose of this study was to investigate the effect of menopausal hormone therapy (MHT) on the risk of Alzheimer disease (AD) by examining its duration, initiation time, routes of administration, and formulations through systematic review and meta-analysis. PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched on March 15, 2023. We selected cohort studies, case-control studies, and randomized controlled trials on the effect of MHT on AD in women. Odds ratio, relative risk, and hazard ratio were extracted. Random-effect models were used to estimate the polled estimates (relative risk [RR] or odds ratio [OR]) and their 95% confidence interval (95% CI). We included 3 randomized controlled trials, 12 cohort studies, and 16 case-control studies. A total of 7,710,379 women were included. Pooled estimates showed that MHT use for 3-5 years (cohort, RR = 0.56, 95% CI: 0.34-0.93) or initiation within 5 years of menopause (cohort, RR = 0.70, 95% CI: 0.49-0.99) reduced the risk of AD. Oral administration reduced AD risk (cohort, RR = 0.42, 95% CI: 0.40-0.44). Combining estrogen and progesterone (case-control, OR = 1.13, 95% CI: 1.05-1.21) or progesterone only (case-control, OR = 1.13, 95% CI: 1.10-1.17) increases AD risk. Tibolone increased AD risk (cohort, RR = 1.04, 95% CI: 1.01-1.07; case-control, OR = 1.07, 95% CI: 1.01-1.14). MHT-protected apolipoprotein E genotype 4 carriers (cohort, RR = 0.13, 95% CI: 0.02-0.90), depressed populations (cohort, RR = 0.85, 95% CI: 0.80-0.90), and Americas (cohort, RR = 0.54, 95% CI: 0.37-0.80; case-control, OR = 0.68, 95% CI: 0.47-0.99) from AD. Using MHT early (within 5 years after menopause) for about 5 years may protect against AD. However, combining estrogen with progesterone, or using progesterone only, could increase AD risk. Oral MHT methods are more effective than transdermal ones in reducing this risk. SIGNIFICANCE STATEMENT: Menopausal hormone therapy (MHT) use within 5 years after menopause could offer protective benefits against Alzheimer disease (AD). A combination of estrogen and progesterone, using progesterone only or tibolone usage was connected with an elevated risk of AD. Oral MHT was more effective than transdermal methods in lowering AD risk. MHT lowered AD risk in apolipoprotein E genotype 4 allele carriers, individuals with depression, and Americans. MHT regimens should be highly personalized.