Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery

Abstract

After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

Fig 1. FDG-PET brain glucose metabolism as a function of endocrine aging.

Top of figure: Statistical parametric maps (SPMs) display reductions in ¹⁸F-fluoro-2-deoxyglucose (FDG) uptake in (A) postmenopausal (MENO) vs. premenopausal women (CNT); (B) perimenopausal (PERI) vs. premenopausal women; and (C) postmenopausal vs. perimenopauseal women. SPMs are represented on color-coded scales (1<z<3; where z>2 correspond to p<0.001) and displayed onto a standardized MRI. Corresponding coordinates and anatomical areas can be found in S1 Table. Bottom of figure: CMRglc extracted from AD-regions by endocrine group. Values are pons-adjusted mean values, SEM; *p<0.01, **p<0.001. Abbreviations: CNT = premenopausal women; PERI = perimenopausal women; MENO = postmenopausal women, SUVR = standardized uptake value ratios (unitless).

Fig 2. Associations between mitochondrial COX activity and FDG-PET brain glucose metabolism.

Top of figure: Statistical parametric maps (SPMs) display positive associations between CMRglc and COX in (A) all subjects, B) postmenopausal women, C) perimenopausal women, and D) premenopausal women. SPMs are represented on color-coded scales (1<z<3; where z>2 correspond to p<0.001) and displayed onto a standardized MRI. Corresponding coordinates and anatomical areas can be found in S2 Table. Bottom of figure: Correlations between CMRglc in AD-regions and mitochondrial COX activity by endocrine group. CMRglc measures are age and pons-adjusted values; COX Vmax are age- and CS-adjusted residuals. All correlations p’s<0.001 except CNT p<0.05. Abbreviations: CNT = premenopausal women; PERI = perimenopausal women; MENO = postmenopausal women.