Age at menopause relates to later‐life hippocampal volume in an APOE4‐specific manner

Abstract

AbstractBackgroundThere are important sex differences in Alzheimer’s disease (AD) including two‐fold higher prevalence and stronger association of the apolipoprotien‐ε e4 allele (APOE4) with AD risk in women versus men. Given the central role of sex hormones in brain structure/function, examining factors influencing lifetime exposure to sex hormones is critical to understanding sex differences in AD. Menopause is characterized by a marked reduction in ovarian hormones, leading to loss of sex hormone‐related neuroprotective effects and AD‐like changes in brain bioenergetics. Earlier age at menopause is associated with higher AD risk; however, the brain mechanisms by which menopausal age contributes to AD etiology and the role of APOE4 in this association are unclear. Among non‐demented, older female participants of the Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohort, we examined the associations of age at menopause with later‐life hippocampal and whole brain volumes and the moderating role of APOE4 in these associations.Method177 postmenopausal women ≥ 60 years of age (age range:60–76, age mean=65.8, 96% White) with MRI volumetric data and APOE4 genotype data were examined. Multivariable linear regressions were used to examine associations of self‐reported age at menopause and its interaction with APOE4 carrier status with hippocampal and whole‐brain volumes. Models were adjusted for intracranial volume, MRI scanner, age, education, BMI at MRI, smoking, age at menarche, number of pregnancies, natural versus surgical menopause and ever‐use of hormone therapy or hormonal contraception.ResultA significant age at menopause × APOE4 interaction on hippocampal volume (p=.05) revealed that earlier age at menopause related to smaller hippocampal volume (p=.016) among APOE4 carriers but not non‐carriers (p=.86; Figure 1). Age at menopause did not relate to whole brain volume regardless of APOE4 status. In the multivariable model, older age, less education and smaller intracranial volume also related to smaller hippocampal volume.ConclusionResults suggest that early menopause may be a risk factor for neurodegeneration among APOE4 carriers particularly in the AD‐sensitive hippocampus. The specificity of this relationship to APOE4 carriers indicates mechanistic interactions between APOE4 and sex hormones and offers a potential contributing factor to the more adverse effect of APOE4 in women.