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.

Towards an understanding of women's brain aging: the immunology of pregnancy and menopause

“…While some women transition through perimenopause without long-term adverse effects beyond normal aging processes, this period may also involve an increased risk of accelerated neurological decline [37]. The transition to menopause is characterized by neural changes such as decline in brain glucose metabolism [42], reduction in gray and white matter volume in brain regions vulnerable to AD [146,147,148,41], increased amyloid-beta deposition [149], and a wide array of changes in neurological function [37]. All of these processes are highly intertwined.…”

Sex is a defining feature of neuroimaging phenotypes in major brain disorders

“…Finally, age-related estrogen loss at menopause marks a critical transition period in the female lifespan that is linked to changes in brain structure, such as changes in hippocampal volume and cerebral hypometabolism [Mosconi et al, 2018]. However, most of this evidence comes from studies with small sample sizes, and often in populations that are genetically enriched for certain diseases.…”

Dynamic Neuroimmune Profile during Mid-life Aging in the Female Brain and Implications for Alzheimer Risk

“…The perimenopausal transition in females is marked by a bioenergetic deficit characterized by reduced glucose metabolism in brain as detected by 2-deoxy-2-[ 18 F]fluoro-d-glucose positron emission tomography ( 18 F-FDG-PET) and concomitant downregulation of glucose transporter 3 (GLUT3), pyruvate dehydrogenase 1 (PDH1), and oxidative phosphorylation ( Ding et al., 2013a , 2013b ; Yao and Brinton, 2012 ; Yao et al., 2012 ; Yin et al., 2015 ). Sex-differences in the bioenergetic trajectory of aging are apparent in both mechanistic and clinical analyses ( Mosconi et al., 2017b , 2018 ; Yin et al., 2015 ; Zhao et al., 2016 ). Metabolic decline in the brain is an early indicator of the prodromal phase of AD and can be an initiator of chronic inflammation, which is involved in the pathophysiology of the disease ( Wang et al., 2020 ; Yin et al., 2015 , 2016 ).…”