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

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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
Pages (from-to)989-998
Number of pages10
JournalJAMA Neurology
Issue number8
StatePublished - Aug 1 2018

Bibliographical note

Funding Information:
part by grants K01 AG049164, K12 HD043483, K24 AG046373, HHSN311201600276P, R01 AG034962, R01 HL111516, R01 NS100980, R01 AG056534, P30 AG10161, RF1 AG15819, R01 AG17917, R01 AG30146, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146, R01 AG027161, R01 AG021155, R01 AG037639, U01 AG46152, U01 AG006781, U01 AG032984, U01 HG004610, U01 HG006375, U24 AG021886, and U24 AG041689 from the Intramural Research Program, the National Institute on Aging, the National Institutes of Health, and the Vanderbilt Memory and Alzheimer’s Center. The National Alzheimer’s Coordinating Center database is funded by the National Institute on Aging and National Institutes of Health grant U01 AG016976. National Alzheimer’s Coordinating Center data are contributed by the National Institute of Aging– funded Alzheimer’s Disease Centers: P30 AG019610 (principal investigator [PI], Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI, Scott Small, MD), P50 AG025688 (PI, Allan Levey, MD, PhD), P30 AG010133 (PI, Andrew Saykin, PsyD), P50 AG005146 (PI, Marilyn Albert, PhD), P50 AG005134 (PI, Bradley Hyman, MD, PhD), P50 AG016574 (PI, Ronald Petersen, MD, PhD), P50 AG005138 (PI, Mary Sano, PhD), P30 AG008051 (PI, Steven Ferris, PhD), P30 AG013854 (PI, M. Marsel Mesulam, MD), P30 AG008017 (PI, Jeffrey Kaye, MD), P30 AG010161 (PI, David Bennett, MD), P30 AG010129 (PI, Charles DeCarli, MD), P50 AG016573 (PI, Frank LaFerla, PhD), P50 AG016570 (PI, David Teplow, PhD), P50 AG005131 (PI, Douglas Galasko, MD), P50 AG023501 (PI, Bruce Miller, MD), P30 AG035982 (PI, Russell Swerdlow, MD), P30 AG028383 (PI, Linda Van Eldik, PhD), P30 AG010124 (PI, John Trojanowski, MD, PhD), P50 AG005133 (PI, Oscar Lopez, MD), P50 AG005142 (PI, Helena Chui, MD), P30 AG012300 (PI, Roger Rosenberg, MD), P50 AG005136 (PI, Thomas Grabowski, MD, PhD), P50 AG033514 (PI, Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI, John Morris, MD). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (National Institutes of Health grant U01 AG024904) and US Department of Defense ADNI award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb Company, CereSpir Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research and Development LLC, Johnson and Johnson Pharmaceutical Research and Development LLC, Lumosity, Lundbeck, Merck and Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Company, and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. The ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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ASJC Scopus subject areas

  • Clinical Neurology


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