Increased Alzheimer's risk during the menopause transition: A 3-year longitudinal brain imaging study

Abstract

Two thirds of all persons with late-onset Alzheimer's disease (AD) are women. Identification of sex-based molecular mechanisms underpinning the female-based prevalence of AD would advance development of therapeutic targets during the prodromal AD phase when prevention or delay in progression is most likely to be effective. This 3-year brain imaging study examines the impact of the menopausal transition on Alzheimer's disease (AD) biomarker changes [brain β-amyloid load via 11C-PiB PET, and neurodegeneration via 18F-FDG PET and structural MRI] and cognitive performance in midlife. Fifty-nine 40-60 year-old cognitively normal participants with clinical, neuropsychological, and brain imaging exams at least 2 years apart were examined. These included 41 women [15 premenopausal controls (PRE), 14 perimenopausal (PERI), and 12 postmenopausal women (MENO)] and 18 men. We used targeted minimum loss-based estimation to evaluate AD biomarker and cognitive changes. Older age was associated with baseline Aβ and neurodegeneration markers, but not with rates of change in these biomarkers. APOE4 status influenced change in Aβ load, but not neurodegenerative changes. Longitudinally, MENO and PERI groups showed declines in estrogen-dependent memory tests as compared to men (p < .04). Adjusting for age, APOE4 status, and vascular risk confounds, the MENO and PERI groups exhibited higher rates of CMRglc decline as compared to males (p ≤ .015). The MENO group exhibited the highest rate of hippocampal volume loss (p's ≤ .001), and higher rates of Aβ deposition than males (p < .01). CMRglc decline exceeded Aβ and atrophy changes in all female groups vs. men. These findings indicate emergence and progression of a female-specific hypometabolic AD-endophenotype during the menopausal transition. These findings suggest that the optimal window of opportunity for therapeutic intervention to prevent or delay progression of AD endophenotype in women is early in the endocrine aging process.

Fig 1. ROC curves showing group separation as predicted by AD biomarkers.

A) MENO vs. males; B) PERI vs. males; C) PRE vs Men; D) MENO vs PERI; E) MENO vs PRE. Graphs show group separation as predicted by 3-year changes in FDG-PET CMRglc in frontal cortex (blue; age-adjusted measures), PiB-PET amyloid load in frontal cortex (orange; age-adjusted measures), and hippocampal volume (green; age and TIV-adjusted measures).

Fig 2. Baseline and follow-up FDG-PET scans in 4 representative cases.

Top left: A 52 year-old woman (14 years education, APOE 3/4 carrier, CDR 0, MMSE 30) who was premenopausal at baseline and became perimenopausal by the follow-up exam. Top right: A 43 year-old woman (16 years education, APOE 3/3 carrier, CDR 0, MMSE 29) who was perimenopausal at baseline and became postmenopausal by the follow-up exam. Bottom left: A 59 year-old woman (16 years education, APOE 3/3 carrier, CDR 0, MMSE 30) who was postmenopausal at baseline. Bottom right: A 55 year-old man (14 years education, APOE 3/4 carrier, CDR 0, MMSE 30). Arrows point to areas of progressive CMRglc reductions in the follow-up vs. baseline scans. FDG measures are standardized uptake volume ratios (SUVR) adjusted for global uptake.