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.
Highlights
Female sex is a major risk factor for developing late-onset Alzheimer’s disease (AD)[1]
Preclinical evidence has implicated a shift in the glucose bioenergetic system of the brain during the perimenopause to menopause transition (PTMT) as an early initiating mechanism[4]
In our earlier cross-sectional analyses[13],[14], multi-modality brain imaging detected emergence of a female-specific AD-endophenotype characterized by decreased brain glucose bioenergetics, increased Aβ deposition, and gray volume loss in PERI and MENO women
Summary
Female sex is a major risk factor for developing late-onset Alzheimer’s disease (AD)[1]. Women of menopausal age showed reduced gray matter volumes in parietal and temporal regions, including medial temporal cortex, as compared to men[13] It remains to be established whether these biomarker abnormalities are progressive, and indicative of an ongoing AD process. We report 3-year follow-up brain imaging observations of the previously studied cohorts This observational longitudinal study characterizes progression of well-established AD-biomarkers [11C-PiB PET Aβ deposition, and neurodegeneration via 18F-FDG PET glucose metabolism and MRI atrophy], in cognitively normal women at different endocrine transition stages (pre-menopause, perimenopause, menopause), and men, adjusted by age and other potential confounders
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