MR study finds no causal link between age at menarche or age at menopause and Alzheimer's risk

Reviewed by Emily Henderson, B.Sc.Oct 5 2021

Aging-US published "The role of age at menarche and age at menopause in Alzheimer's disease: evidence from a bidirectional mendelian randomization study" which reported that the association between endogenous estrogen exposure and Alzheimer's disease remains inconclusive in previous observational studies, and few Mendelian randomization studies have focused on their causality thus far.

The MR analyses indicated no significant causal relationship between the genetically determined age at menarche or age at menopause and AD risk. In contrast, an inverse association was detected between age at menarche and body mass index.

As the population ages, almost 115.4 million people worldwide will have dementia by 2050, with the main cause being Alzheimer's disease."

Dr. Zengnan Mo, Center for Genomic and Personalized Medicine, Guangxi Medical University

Notably, women have a more than 55% greater lifetime risk of AD at age 65 than men and constitute two-thirds of late-onset AD cases. In recent years, sex hormones, especially estrogen, have gained increasing attention because accumulating population-based evidence has proposed a protective role for exogenous hormone replacement therapy in cognitive decline and dementia progression in postmenopausal females. For example, a large, diverse cohort study showed that delayed menarche increased dementia risk, but this association disappeared after adjusting for baseline risk factors of dementia in other studies.

Similarly, inconsistent estimates ranged from a modest elevated dementia or AD risk with early onset of natural menopause to an inverse association or an entire loss of statistical evidence.

As genetic variants are allocated randomly at the time of conception and are relatively independent of environmental and lifestyle factors, the typical confounding factors or reverse causation limited from observational studies could be better mitigated. Nevertheless, MR analysis can provide indirect evidence for a causal association relying on the following three core assumptions the IVs should be robustly correlated with exposure the IVs should be independent of any confounders of the exposure-outcome association the IVs affect the risk of outcome only through the exposure, rather than any alternative pathways.

The Mo Research Team concluded in their Aging-US Research Output, "our bidirectional MR study provided no evidence for a causal effect of the genetically determined age at menarche or age at menopause on AD susceptibility, or vice versa. In contrast, earlier menarche might be associated with higher adult BMI. Further studies combining individual epidemiological and genetic data are warranted to validate and replicate these findings."