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. 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

Timothy J Hohman  1 , Logan Dumitrescu  1 , Lisa L Barnes  2 , Madhav Thambisetty  3 , Gary Beecham  4   5 , Brian Kunkle  5 , Katherine A Gifford  1 , William S Bush  6 , Lori B Chibnik  7   8 , Shubhabrata Mukherjee  9 , Philip L De Jager  10   11 , Walter Kukull  12 , Paul K Crane  9 , Susan M Resnick  3 , C Dirk Keene  13 , Thomas J Montine  14 , Gerard D Schellenberg  15 , Jonathan L Haines  7 , Henrik Zetterberg  16   17   18 , Kaj Blennow  16   17   19 , Eric B Larson  9   20 , Sterling C Johnson  21 , Marilyn Albert  22 , David A Bennett  2 , Julie A Schneider  2 , Angela L Jefferson  1 ; Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative
Affiliations

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

Timothy J Hohman et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Larson reports royalties from UpToDate. Dr Schneider reports personal fees from Avid Radiopharmaceuticals and Navidea Biopharmaceuticals outside the submitted work. Dr Zetterberg has served at advisory boards of Eli Lilly, Roche Diagnostics, and Pharmasum Therapeutics and is one of the founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures–based platform company at the University of Gothenburg. Dr Blennow has served at advisory boards of Alzheon, Eli Lilly, IBL International, Fujirebio, Merck, and Roche Diagnostics and is one of the founders of Brain Biomarker Solutions in Gothenburg AB.

Figures

Figure 1.
Figure 1.. APOE Interaction With Sex on CSF Total Tau
Forest plot summarizing the analysis of APOE ε4 × sex interactions on CSF total tau modeled as a continuous outcome. Squares represent standardized β of the interaction term within each data set; confidence interval is represented by the line segment. The size of the square indicates precision of the estimate based on study variance. The fixed-effect β is represented by the diamond at the bottom of the figure. BIOCARD indicates Biomarkers of Cognitive Decline Among Normal Individuals; WRAP, Wisconsin Registry of Alzheimer’s Prevention; ADNI, Alzheimer’s Disease Neuroimaging Initiative; VMAP, Vanderbilt Memory and Aging Project.
Figure 2.
Figure 2.. APOE Association With CSF Total Tau Stratified by Sex
A, APOE-ε4 association with CSF tau in men. B, APOE-ε4 association with CSF tau in women. Forest plot summarizing the sex-stratified analysis of APOE ε4 on CSF total tau modeled as a continuous outcome. Squares represent standardized β of the APOE ε4 term within each data set; confidence interval is represented by the line segment. The size of the square indicates precision of the estimate based on study variance. The fixed-effect β is represented by the diamond at the bottom of the figure. BIOCARD indicates Biomarkers of Cognitive Decline Among Normal Individuals; WRAP, Wisconsin Registry of Alzheimer’s Prevention; ADNI, Alzheimer’s Disease Neuroimaging Initiative; VMAP, Vanderbilt Memory and Aging Project.
See this image and copyright information in PMC

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