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Original Investigation
August 2018

Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau

Author Affiliations
  • 1Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, Tennessee
  • 2Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
  • 3Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 4John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, Florida
  • 5Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, Florida
  • 6Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio
  • 7Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 8Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 9Department of Medicine, University of Washington, Seattle
  • 10Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York
  • 11Cell Circuits Program, Broad Institute, Cambridge, Massachusetts
  • 12Department of Epidemiology, School of Public Health, University of Washington, Seattle
  • 13Department of Pathology, University of Washington, Seattle
  • 14Department of Pathology, Stanford University, Stanford, California
  • 15Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 16Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
  • 17Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 18Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, England
  • 19UK Dementia Research Institute, London, England
  • 20Kaiser Permanente Washington Health Research Institute, Seattle
  • 21Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison
  • 22Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Neurol. 2018;75(8):989-998. doi:10.1001/jamaneurol.2018.0821
Key Points

Question  Does the association between apolipoprotein E (APOE) and Alzheimer disease neuropathology differ by sex?

Findings  In this multicohort study, women showed a stronger association between APOE and cerebrospinal fluid tau levels when compared with men, particularly among amyloid-positive individuals. There was no sex difference in the association between APOE and amyloidosis or between APOE and autopsy measures of neurofibrillary tangles.

Meaning  The sex difference in the association between APOE and cerebrospinal fluid measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

Abstract

Importance  The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.

Objective  To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy.

Design, Setting, and Participants  This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017.

Main Outcomes and Measures  Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer’s Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles.

Results  Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95% CI, −0.18 to 0.31; P = .62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden.

Conclusions and Relevance  We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

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