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

<div><p>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.</p></div

Demographic and clinical characteristics by clinical group.

<p>Demographic and clinical characteristics by clinical group.</p

Group separation as predicted by bioenergetic measures.

<p>Group separation as predicted by bioenergetic measures.</p

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

<p><b><i>Top of figure</i></b>: 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 (12 correspond to p<0.001) and displayed onto a standardized MRI. Corresponding coordinates and anatomical areas can be found in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185926#pone.0185926.s002" target="_blank">S2 Table</a>. <i>Bottom of figure</i></b>: 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.</p

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

<p><b><i>Top of figure</i></b>: 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 (12 correspond to p<0.001) and displayed onto a standardized MRI. Corresponding coordinates and anatomical areas can be found in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185926#pone.0185926.s001" target="_blank">S1 Table</a>. <i>Bottom of figure</i></b>: 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).</p

Relationship between age quartiles, Aβ₄₂ and X-tau in 3 cohorts combined.

<p>Scatter plots by age quartiles with the x-axis showing for Aβ₄₂ the combined z scores and raw values by cohort. The y-axis shows the log transformed P-tau181 and T-tau raw scores by cohort and the combined z scores. Individual subjects are shown as circles for NYU, triangles for ADNI and squares for NACC. The outcome groups are indicated by color with the cross-sectional NL in blue, Stable NC in gray, and Future MCI/AD in orange. For each quartile, the linear fit is shown as a solid light blue line and the quadratic fit as a solid red line. The shaded area represents the area outside the 95% CI of the Aβ₄₂ values for each quartile and the vertical dotted line is at the mean Aβ₄₂ for each quartile.</p

Aβ₄₂ in the prediction of X-tau by age quartiles.

<p>Aβ₄₂ in the prediction of X-tau by age quartiles.</p

Subject flow chart.

<p>The patient flow chart shows the inclusion and exclusions of subjects in the analyses conducted for this study.</p

Relationship of X-tau with Aβ₃₈ and Aβ₄₀.

<p>Scatter plots for n = 233 depicting Aβ₃₈ and Aβ₄₀ on the x-axis and the natural log transformation of X-Tau (and the associated raw values) on the y-axis. The outcome groups are indicated by color with the cross-sectional NL in blue, Stable NC in gray, and Future MCI/AD in orange. The linear fit is shown as a solid light blue line.</p

Demographics and baseline descriptive variables for outcome groups.

<p>Demographics and baseline descriptive variables for outcome groups.</p