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

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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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The record

Venue

JAMA Neurology

Topic

Dementia and Cognitive Impairment Research

Field

Medicine

Canadian institutions

—

Funders

University of Colorado School of Medicine, Anschutz Medical CampusJanssen Alzheimer Immunotherapy Research And DevelopmentJohnson and Johnson Pharmaceutical Research and DevelopmentEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institute of Neurological Disorders and StrokeNational Institute of Biomedical Imaging and BioengineeringNational Human Genome Research InstituteNational Institute on AgingFeinberg School of MedicineUniversity of Texas Health Science Center at San AntonioPerelman School of Medicine, University of PennsylvaniaCanadian Institutes of Health ResearchPfizerUniversity of WashingtonUniversity of California, Los AngelesNational Institutes of HealthIXICOGeriatric Research Education and Clinical CenterH. Lundbeck A/SServierFoundation for the National Institutes of HealthUniversity of Southern CaliforniaEisaiUniversity of TorontoParkinson's UKNorthern California Institute for Research and EducationGenentechNational Alzheimer's Coordinating CenterUniversity of South FloridaF. Hoffmann-La RocheRush UniversityJohns Hopkins UniversityVanderbilt Memory and Alzheimer's CenterYork UniversityUniversity of North TexasAlzheimer's Disease Neuroimaging InitiativeNorthwestern UniversityBiogenUniversity of MiamiBioClinicaEli Lilly and CompanyTexas Tech UniversityEmory UniversityUniversity of PennsylvaniaBristol-Myers SquibbU.S. Department of DefenseVanderbilt UniversityMassachusetts General HospitalNational Heart, Lung, and Blood InstituteNational Center for Advancing Translational SciencesNovartis Pharmaceuticals CorporationAlzheimer's AssociationNIH Clinical CenterUniversity of California, IrvineMeso Scale Diagnostics

Keywords

NeuropathologyApolipoprotein ECohortBiomarkerAlzheimer's diseaseInternal medicineOncologyCerebrospinal fluidPopulationMedicinePathologyPsychologyDiseaseBiologyGenetics

Has abstract in OpenAlex

yes

API

/api/v1/works/W2802157723