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

Publication ,  Journal Article
Hohman, TJ; Dumitrescu, L; Barnes, LL; Thambisetty, M; Beecham, G; Kunkle, B; Gifford, KA; Bush, WS; Chibnik, LB; Mukherjee, S; De Jager, PL ...
Published in: JAMA Neurol
August 1, 2018

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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Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

August 1, 2018

Volume

75

Issue

8

Start / End Page

989 / 998

Location

United States

Related Subject Headings

  • tau Proteins
  • Sex Factors
  • Plaque, Amyloid
  • Phosphoproteins
  • Peptide Fragments
  • Neurofibrillary Tangles
  • Male
  • Humans
  • Genotype
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hohman, T. J., Dumitrescu, L., Barnes, L. L., Thambisetty, M., Beecham, G., Kunkle, B., … Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative, . (2018). Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol, 75(8), 989–998. https://doi.org/10.1001/jamaneurol.2018.0821
Hohman, Timothy J., Logan Dumitrescu, Lisa L. Barnes, Madhav Thambisetty, Gary Beecham, Brian Kunkle, Katherine A. Gifford, et al. “Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.JAMA Neurol 75, no. 8 (August 1, 2018): 989–98. https://doi.org/10.1001/jamaneurol.2018.0821.
Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018 Aug 1;75(8):989–98.
Hohman, Timothy J., et al. “Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.JAMA Neurol, vol. 75, no. 8, Aug. 2018, pp. 989–98. Pubmed, doi:10.1001/jamaneurol.2018.0821.
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, Keene CD, Montine TJ, Schellenberg GD, Haines JL, Zetterberg H, Blennow K, Larson EB, Johnson SC, Albert M, Bennett DA, Schneider JA, Jefferson AL, Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018 Aug 1;75(8):989–998.

Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

August 1, 2018

Volume

75

Issue

8

Start / End Page

989 / 998

Location

United States

Related Subject Headings

  • tau Proteins
  • Sex Factors
  • Plaque, Amyloid
  • Phosphoproteins
  • Peptide Fragments
  • Neurofibrillary Tangles
  • Male
  • Humans
  • Genotype
  • Female