Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau

Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

21 Citations (Scopus)

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-e4 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-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-e4 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.

Original languageEnglish (US)
Pages (from-to)989-998
Number of pages10
JournalJAMA Neurology
Volume75
Issue number8
DOIs
StatePublished - Aug 1 2018

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Apolipoproteins
Apolipoproteins E
Cerebrospinal Fluid
Alzheimer Disease
Neurofibrillary Tangles
Sex Characteristics
Autopsy
Apolipoprotein E4
Amyloid
Amyloid Plaques
Biomarkers
Amyloidosis
Longitudinal Studies
Registries
Cohort Studies
Alleles
Genotype
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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 Neurology, 75(8), 989-998. https://doi.org/10.1001/jamaneurol.2018.0821
Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative. / Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau. In: JAMA Neurology. 2018 ; Vol. 75, No. 8. pp. 989-998.
@article{b0a4eda9ad4b46dbb7a53f81f319b932,
title = "Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau",
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-e4 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-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-e4 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.",
author = "{Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative} and Hohman, {Timothy J.} and Logan Dumitrescu and Barnes, {Lisa L.} and Madhav Thambisetty and Gary Beecham and Brian Kunkle and Gifford, {Katherine A.} and Bush, {William S.} and Chibnik, {Lori B.} and Shubhabrata Mukherjee and {De Jager}, {Philip L.} and Walter Kukull and Crane, {Paul K.} and Resnick, {Susan M.} and Keene, {C. Dirk} and Montine, {Thomas J.} and Schellenberg, {Gerard D.} and Haines, {Jonathan L.} and Henrik Zetterberg and Kaj Blennow and Larson, {Eric B.} and Johnson, {Sterling C.} and Marilyn Albert and Bennett, {David A.} and Schneider, {Julie A.} and Jefferson, {Angela L.} and Kaj Blennowe and Erin Abner and Perrie Adams and Roger Albin and Liana Apostolova and Steven Arnold and Sanjay Asthana and Craig Atwood and Clinton Baldwin and Robert Barber and Sandra Barral and Thomas Beach and James Becker and Duane Beekly and Eileen Bigio and Bigio, {Eileen H} and Deborah Blacker and Bradley Boeve and James Bowen and Adam Boxer and James Burke and Jeffrey Burns and Marek-Marsel Mesulam and Sandra Weintraub",
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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 Neurology, vol. 75, no. 8, pp. 989-998. https://doi.org/10.1001/jamaneurol.2018.0821

Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau. / Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative.

In: JAMA Neurology, Vol. 75, No. 8, 01.08.2018, p. 989-998.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau

AU - Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative

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 - Blennowe, Kaj

AU - Abner, Erin

AU - Adams, Perrie

AU - Albin, Roger

AU - Apostolova, Liana

AU - Arnold, Steven

AU - Asthana, Sanjay

AU - Atwood, Craig

AU - Baldwin, Clinton

AU - Barber, Robert

AU - Barral, Sandra

AU - Beach, Thomas

AU - Becker, James

AU - Beekly, Duane

AU - Bigio, Eileen

AU - Bigio, Eileen H

AU - Blacker, Deborah

AU - Boeve, Bradley

AU - Bowen, James

AU - Boxer, Adam

AU - Burke, James

AU - Burns, Jeffrey

AU - Mesulam, Marek-Marsel

AU - Weintraub, Sandra

PY - 2018/8/1

Y1 - 2018/8/1

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-e4 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-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-e4 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.

AB - 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-e4 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-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-e4 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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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 Neurology. 2018 Aug 1;75(8):989-998. https://doi.org/10.1001/jamaneurol.2018.0821