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JAMA Neurol DOI:10.1001/jamaneurol.2018.0821

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

Publication TypeJournal Article
Year of Publication2018
AuthorsHohman, 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 AuthorsAlzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative
JournalJAMA Neurol
Volume75
Issue8
Pages989-998
Date Published2018 08 01
ISSN2168-6157
KeywordsAged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Cohort Studies, Female, Genotype, Humans, Male, Neurofibrillary Tangles, Peptide Fragments, Phosphoproteins, Plaque, Amyloid, Sex Factors, tau Proteins
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.

DOI10.1001/jamaneurol.2018.0821
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29801024?dopt=Abstract

Alternate JournalJAMA Neurol
PubMed ID29801024
PubMed Central IDPMC6142927
Grant ListR01 AG021155 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
UL1 TR002369 / TR / NCATS NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
RF1 AG059869 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P50 AG047366 / AG / NIA NIH HHS / United States
P30 AG035982 / AG / NIA NIH HHS / United States
R01 HL111516 / HL / NHLBI NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
UL1 TR000445 / TR / NCATS NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 AG037639 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 NS100980 / NS / NINDS NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG033514 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
U19 AG033655 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
R01 AG056534 / AG / NIA NIH HHS / United States
/ / CIHR / Canada
U24 AG041689 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
K23 AG045966 / AG / NIA NIH HHS / United States
S10 OD023680 / OD / NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
K01 AG049164 / AG / NIA NIH HHS / United States
R01 AG027161 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
UL1 TR002243 / TR / NCATS NIH HHS / United States
K24 AG046373 / AG / NIA NIH HHS / United States
P30 AG013854 / AG / NIA NIH HHS / United States
K12 HD043483 / HD / NICHD NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
R01 AG034962 / AG / NIA NIH HHS / United States
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