Sex-driven modifiers of Alzheimer’s risk: a multi-modality brain imaging study

Objective: To investigate sex differences in late-onset Alzheimer’s
disease (AD) risks by means of multi-modality brain biomarkers [β-amyloid
load via 11C-PiB PET, and neurodegeneration via 18F-FDG PET and structural
MRI]. Methods: We examined 121 cognitively normal participants [85 women
and 36 men] ages 40-65, with clinical, laboratory, neuropsychological,
lifestyle exams, and MRI, FDG- and PiB-PET exams. Several clinical (e.g.
age, education, APOE status, family history), medical (e.g., depression,
diabetes, 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 LASSO
regressions were used to compare AD-biomarkers between men and women, and
to identify the risk factors associated with sex-related differences.
Results: Groups were comparable on clinical and cognitive measures.
Adjusting 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, FWE-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 using 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. Conclusion: Hormonal risk factors, in particular menopause,
predict AD-endophenotype in middle-aged women. These findings
suggest that the window of opportunity for AD-preventative
interventions in women is early in the endocrine aging process.