Sex-driven modifiers of Alzheimer risk

Abstract

ObjectiveTo investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (β-amyloid load via 11C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI).MethodsWe examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences.ResultsGroups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB β-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group (p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease.ConclusionHormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.

Menopause Impacts Human Brain Structure, Connectivity, Energy Metabolism, and Amyloid-beta Deposition.

“…Consistent with previous studies of MT women at risk for AD [9][10][11] , our POST and PERI APOE-4 carriers exhibited higher Aβ deposition compared to age-matched males. While Aβ deposition was mild, these data support evidence that interactions between age, female gender and APOE-4 increase AD vulnerability during perimenopause 32 .…”

“…The MT also impacted brain energetics on multiple levels. The POST group, and to a lesser extent the PERI group, exhibited hypometabolism in parieto-temporal cortices, consistent with previous reports in women at risk for AD [9][10][11] . However, in the present study, regional CMRglc largely plateaued postmenopause, suggesting adaptation to a new metabolic baseline after prolonged estrogen de ciency.…”

“…We examined MT-stage effects on a panel of biomarkers examining brain (a) structure: MRI-based gray and white matter volume (GMV, WMV) and fractional anisotropy (FA, an index of WM integrity and structural connectivity 12 ); (b) energy metabolism: 18 F-FDG PET glucose metabolism (CMRglc), ASL cerebral blood ow (CBF), and 31 P-MRS ATP production; and (c) 11 C-PiB-PET Aβ deposition. Unless otherwise speci ed, all results are signi cant at p < 0.05, cluster-level corrected for family-wise type error (FWE), adjusted for age, APOE-4 status, and modality-speci c confounders.…”

“…stroke, any neurodegenerative diseases, major psychiatric disorders, hydrocephalus, intracranial mass and infarcts on MRI), use of psychoactive medications, and contraindications to MRI or PET. Participants had Mini Mental Status Exam ≥ 27 and normal cognitive performance for age and education [9][10][11] .…”

Thyroid hormone: sex-dependent role in nervous system regulation and disease

“…Intebi et al studied some of the plasma markers in an AD cohort; however, they could not identify any change in circulating T3 and TSH levels between male and female AD patients [ 106 ]. However, in another study, female sex and thyroid dysfunction were correlated with AD endophenotype in the middle-aged population [ 107 ]. Further mechanistic understanding is needed to have a clear view on this aspect.…”