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

TitleIncreased Alzheimer's risk during the menopause transition: A 3-year longitudinal brain imaging study.
Publication TypeJournal Article
Year of Publication2018
AuthorsMosconi L, Rahman A, Diaz I, Wu X, Scheyer O, Hristov HWebb, Vallabhajosula S, Isaacson RS, de Leon MJ, Brinton RDiaz
JournalPLoS One
Date Published2018
KeywordsAged, Alzheimer Disease, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Brain, Cognitive Dysfunction, Disease Progression, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Memory, Menopause, Middle Aged, Neuroimaging, Neuropsychological Tests, Positron-Emission Tomography

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.

Alternate JournalPLoS ONE
PubMed ID30540774
PubMed Central IDPMC6291073
Grant ListP01 AG026572 / AG / NIA NIH HHS / United States
R01 AG057931 / AG / NIA NIH HHS / United States

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