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Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.
JAMA Neurol 2018; 75(8):989-998JN

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.

Authors+Show Affiliations

Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee.Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee.Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.John T MacDonald Foundation Department of Human Genetics, University of Miami, Miami, Florida. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, Florida.Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, Florida.Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee.Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Department of Medicine, University of Washington, Seattle.Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York. Cell Circuits Program, Broad Institute, Cambridge, Massachusetts.Department of Epidemiology, School of Public Health, University of Washington, Seattle.Department of Medicine, University of Washington, Seattle.Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.Department of Pathology, University of Washington, Seattle.Department of Pathology, Stanford University, Stanford, California.Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. UK Dementia Research Institute, London, England.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, England.Department of Medicine, University of Washington, Seattle. Kaiser Permanente Washington Health Research Institute, Seattle.Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison.Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, Maryland.Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

29801024

Citation

Hohman, Timothy J., et al. "Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau." JAMA Neurology, vol. 75, no. 8, 2018, pp. 989-998.
Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018;75(8):989-998.
Hohman, T. J., Dumitrescu, L., Barnes, L. L., Thambisetty, M., Beecham, G., Kunkle, B., ... Jefferson, A. L. (2018). Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurology, 75(8), pp. 989-998. doi:10.1001/jamaneurol.2018.0821.
Hohman TJ, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018 08 1;75(8):989-998. PubMed PMID: 29801024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. AU - Hohman,Timothy J, AU - Dumitrescu,Logan, AU - Barnes,Lisa L, AU - Thambisetty,Madhav, AU - Beecham,Gary, AU - Kunkle,Brian, AU - Gifford,Katherine A, AU - Bush,William S, AU - Chibnik,Lori B, AU - Mukherjee,Shubhabrata, AU - De Jager,Philip L, AU - Kukull,Walter, AU - Crane,Paul K, AU - Resnick,Susan M, AU - Keene,C Dirk, AU - Montine,Thomas J, AU - Schellenberg,Gerard D, AU - Haines,Jonathan L, AU - Zetterberg,Henrik, AU - Blennow,Kaj, AU - Larson,Eric B, AU - Johnson,Sterling C, AU - Albert,Marilyn, AU - Bennett,David A, AU - Schneider,Julie A, AU - Jefferson,Angela L, AU - ,, PY - 2018/5/26/pubmed PY - 2019/10/18/medline PY - 2018/5/26/entrez SP - 989 EP - 998 JF - JAMA neurology JO - JAMA Neurol VL - 75 IS - 8 N2 - 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/29801024/Sex_Specific_Association_of_Apolipoprotein_E_With_Cerebrospinal_Fluid_Levels_of_Tau_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2018.0821 DB - PRIME DP - Unbound Medicine ER -