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July 14, 2020; 95 (2) Article

Sex-driven modifiers of Alzheimer risk

A multimodality brain imaging study

Aneela Rahman, Eva Schelbaum, Katherine Hoffman, Ivan Diaz, Hollie Hristov, Randolph Andrews, Steven Jett, Hande Jackson, Andrea Lee, Harini Sarva, Silky Pahlajani, Dawn Matthews, View ORCID ProfileJonathan Dyke, Mony J. de Leon, Richard S. Isaacson, Roberta D. Brinton, Lisa Mosconi
First published June 24, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009781
Aneela Rahman
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Eva Schelbaum
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Katherine Hoffman
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Ivan Diaz
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Hollie Hristov
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Randolph Andrews
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Steven Jett
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Hande Jackson
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Andrea Lee
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Harini Sarva
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Silky Pahlajani
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Dawn Matthews
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Jonathan Dyke
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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  • ORCID record for Jonathan Dyke
Mony J. de Leon
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Richard S. Isaacson
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Roberta D. Brinton
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Lisa Mosconi
From the Departments of Neurology (A.R., E.S., I.D., H.H., S.J., H.J., A.L., H.S., S.P., R.S.I., L.M.) and Radiology (J.D., M.J.d.L., L.M.), Weill Cornell Medical College; Division of Biostatistics and Epidemiology (K.H., I.D.), Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY; ADM Diagnostics (R.A., D.M.), Chicago, IL; and Departments of Pharmacology and Neurology (R.D.B.), College of Medicine, University of Arizona, Tucson.
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Citation
Sex-driven modifiers of Alzheimer risk
A multimodality brain imaging study
Aneela Rahman, Eva Schelbaum, Katherine Hoffman, Ivan Diaz, Hollie Hristov, Randolph Andrews, Steven Jett, Hande Jackson, Andrea Lee, Harini Sarva, Silky Pahlajani, Dawn Matthews, Jonathan Dyke, Mony J. de Leon, Richard S. Isaacson, Roberta D. Brinton, Lisa Mosconi
Neurology Jul 2020, 95 (2) e166-e178; DOI: 10.1212/WNL.0000000000009781

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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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