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Abstract
Objective To 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).
Methods We 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.
Results Groups 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.
Conclusion Hormonal 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.
Glossary
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- FDG=
- fluorodeoxyglucose;
- FWE=
- family-wise error;
- GMV=
- gray matter volume;
- HDL=
- high-density lipoprotein;
- HRT=
- hormonal replacement therapy;
- IPL=
- inferior parietal lobule;
- LASSO=
- least absolute shrinkage and selection operator;
- MFG=
- medial frontal gyrus;
- MT=
- menopause transition;
- PiB=
- Pittsburgh compound B;
- SFG=
- superior frontal gyrus;
- SPM=
- Statistical Parametric Mapping;
- WMV=
- white matter volume
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
CME Course: NPub.org/cmelist
- Received August 29, 2019.
- Accepted in final form December 17, 2019.
- © 2020 American Academy of Neurology
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