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 - 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 - Bird, Thomas
AU - Blacker, Deborah
AU - Boeve, Bradley
AU - Bowen, James
AU - Boxer, Adam
AU - Burke, James
AU - Burns, Jeffrey
AU - Fardo, David
AU - Van Eldik, Linda
N1 - Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
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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U2 - 10.1001/jamaneurol.2018.0821
DO - 10.1001/jamaneurol.2018.0821
M3 - Article
C2 - 29801024
AN - SCOPUS:85052691775
SN - 2168-6149
VL - 75
SP - 989
EP - 998
JO - JAMA Neurology
JF - JAMA Neurology
IS - 8
ER -