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Original Investigation
February 4, 2019

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured By Positron Emission Tomography in Clinically Normal Older Adults

Author Affiliations
  • 1Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 3The Florey Institute, The University of Melbourne, Victoria, Australia
  • 4Melbourne School of Psychological Science, University of Melbourne, Victoria, Australia
  • 5Department of Neurology, Stanford University, Stanford, California
  • 6Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
  • 7Vanderbilt Memory & Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
  • 8Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley
  • 9Department of Neurology, Cliniques Universitaires St-Luc, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
  • 10Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, the Netherlands
  • 11Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 12Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 13Department of Nuclear Medicine and Centre for PET, Austin Health, Victoria, Australia
JAMA Neurol. Published online February 4, 2019. doi:10.1001/jamaneurol.2018.4693
Key Points

Questions  Do sex differences exist in regional tauopathy, as measured with positron emission tomography, and is this largely driven by higher global amyloid burden?

Findings  In this study of 2 cross-sectional cohorts of 296 clinically normal adults, women with higher amyloid burden showed greater entorhinal cortical tau signal compared with men with higher amyloid burden. Sex differences did not exist in amyloid load or apolipoprotein E ε4 frequency.

Meaning  In conjunction with this finding, mounting evidence supports the notion that sex differences in the Alzheimer disease pathologic trajectory may well appear downstream of abnormal amyloid burden in the acceleration of tau deposition and brain atrophy.

Abstract

Importance  Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals.

Objective  To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET).

Design, Setting and Participants  This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11–labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer’s Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET.

Main Outcomes and Measures  A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined.

Results  The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = −0.11 [0.05]; 95% CI, −0.21 to −0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = −0.15 [0.09]; 95% CI, −0.32 to 0.01; P = .07).

Conclusions and Relevance  Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

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