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JAMA Neurol. 2018 Aug 1;75(8):989-998. doi: 10.1001/jamaneurol.2018.0821.

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

Author information

Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, Florida.
Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Medicine, University of Washington, Seattle.
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York.
Cell Circuits Program, Broad Institute, Cambridge, Massachusetts.
Department of Epidemiology, School of Public Health, University of Washington, Seattle.
Department of Pathology, University of Washington, Seattle.
Department of Pathology, Stanford University, Stanford, California.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
UK Dementia Research Institute, London, England.
Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, England.
Kaiser Permanente Washington Health Research Institute, Seattle.
Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison.
Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, Maryland.



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.


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.


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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