|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Hohman, TJ, Dumitrescu, L, Barnes, LL, Thambisetty, M, Beecham, G, Kunkle, B, Gifford, KA, Bush, WS, Chibnik, LB, Mukherjee, S, De Jager, PL, Kukull, W, Crane, PK, Resnick, SM, C Keene, D, Montine, TJ, Schellenberg, GD, Haines, JL, Zetterberg, H, Blennow, K, Larson, EB, Johnson, SC, Albert, M, Bennett, DA, Schneider, JA, Jefferson, AL|
|Corporate Authors||Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative|
|Date Published||2018 Aug 01|
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  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
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.
|Alternate Journal||JAMA Neurol|
|PubMed Central ID||PMC6142927|
|Grant List||P30 AG013854 / AG / NIA NIH HHS / United States |
UL1 TR000445 / TR / NCATS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
UL1 TR002369 / TR / NCATS NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U19 AG033655 / AG / NIA NIH HHS / United States
K25 AG055620 / AG / NIA NIH HHS / United States
K23 AG045966 / AG / NIA NIH HHS / United States
P50 AG047366 / AG / NIA NIH HHS / United States
K01 AG049164 / AG / NIA NIH HHS / United States
UL1 TR002243 / TR / NCATS NIH HHS / United States