WashU weekly Neuroscience publications

Sex-specific association of apolipoprotein e with cerebrospinal fluid levels of tau
(2018) JAMA Neurology, 75 (8), pp. 989-998. 

Hohman, T.J.^a , Dumitrescu, L.^a , Barnes, L.L.^{b af} , Thambisetty, M.^c , Beecham, G.^{d e aj} , Kunkle, B.^{e aj} , Gifford, K.A.^a , Bush, W.S.^f , Chibnik, L.B.^{g h} , Mukherjee, S.^{i ak} , De Jager, P.L.^{j k} , Kukull, W.^{l ak} , Crane, P.K.ⁱ , Resnick, S.M.^c , Keene, C.D.^{m ak} , Montine, T.J.ⁿ , Schellenberg, G.D.^o , Haines, J.L.^g , Zetterberg, H.^{p q s} , Blennow, K.^{p q} , Larson, E.B.^{i t} , Johnson, S.C.^u , Albert, M.^{v y} , Bennett, D.A.^b , Schneider, J.A.^b , Jefferson, A.L.^a , Blennowe, K.^{r cc} , Abner, E.^w , Adams, P.^x , Albin, R.^z , Apostolova, L.^aa , Arnold, S.^ab , Asthana, S.^ac , Atwood, C.^ac , Baldwin, C.^ad , Barber, R.^ae , Barral, S.^ag , Beach, T.^ah , Becker, J.^ai , Beekly, D.^ak , Bennett, D.^af , Bigio, E.^al , Bird, T.^ak , Blacker, D.^am , Boeve, B.^an , Bowen, J.^ao , Boxer, A.^ap , Burke, J.^aq , Burns, J.^ar , Buxbaum, J.^as , Cairns, N.^at , Cantwell, L.^ab , Cao, C.^au , Carlson, C.^av , Carlsson, C.^ac , Carney, R.^aj , Carrasquillo, M.^an , Chui, H.^aw , Crane, P.^ak , Cribbs, D.^ax , Crocco, E.^aj , Cruchaga, C.^ay , De Jager, P.^az , DeCarli, C.^ba , Dick, M.^ax , Dickson, D.^an , Doody, R.^bb , Duara, R.^bc , Ertekin-Taner, N.^an , Evans, D.^af , Faber, K.^aa , Fairchild, T.^ae , Fallon, K.^bd , Fardo, D.^w , Farlow, M.^aa , Farrer, L.^ad , Ferris, S.^be , Foroud, T.^aa , Frosch, M.^bf , Galasko, D.^bg , Gearing, M.^bh , Geschwind, D.^bi , Ghetti, B.^aa , Gilbert, J.^aj , Goate, A.^as , Graff-Radford, N.^an , Green, R.^az , Growdon, J.^bf , Haines, J.^bj , Hakonarson, H.^bk , Hamilton, R.^bl , Hamilton-Nelson, K.^aj , Hardy, J.^bm , Harrell, L.^bd , Honig, L.^ag , Huebinger, R.^x , Huentelman, M.^bn , Hulette, C.^aq , Hyman, B.^bf , Jarvik, G.^ak , Jin, L.-W.^ba , Jun, G.^ad , Kamboh, M.I.^bl , Karydas, A.^ap , Katz, M.^bo , Kauwe, J.^bp , Kaye, J.^bq , Kim, R.^ax , Kowall, N.^ad , Kramer, J.^ap , Kuzma, A.^ab , LaFerla, F.^ax , Lah, J.^bh , Larson, E.^ak , Leverenz, J.^br , Levey, A.^bh , Li, G.^bs , Lieberman, A.^z , Lipton, R.^bo , Lopez, O.^bt , Lunetta, K.^ad , Lyketsos, C.^y , Malamon, J.^ab , Marson, D.^bd , Martin, E.^aj , Martiniuk, F.^be , Mash, D.^aj , Masliah, E.^bg , Mayeux, R.^ag , McCormick, W.^ak , McCurry, S.^ak , McDavid, A.^av , McDonough, S.^bu , McKee, A.^ad , Mesulam, M.^al , Miller, B.^ap , Miller, C.^aw , Miller, J.^ba , Montine, T.^ak , Morris, J.^at , Myers, A.^aj , Naj, A.^ab , O’Bryant, S.^ae , Olichney, J.^ba , Parisi, J.^an , Paulson, H.^z , Pericak-Vance, M.^aj , Peskind, E.^bv , Petersen, R.^an , Pierce, A.^ax , Poon, W.^ax , Potter, H.^bw , Qu, L.^ab , Quinn, J.^bq , Raj, A.^au , Raskind, M.^bv , Reiman, E.^bn , Reisberg, B.^be , Reisch, J.^x , Reitz, C.^ag , Ringman, J.^aw , Roberson, E.^bd , Rogaeva, E.^bx , Rosen, H.^ap , Rosenberg, R.^by , Royall, D.^bz , Sager, M.^ac , Sano, M.^as , Saykin, A.^aa , Schellenberg, G.^ab , Schneider, J.^af , Schneider, L.^aw , Seeley, W.^ap , Smith, A.^au , Sonnen, J.^ak , Spina, S.^aa , St George-Hyslop, P.^bx , Stern, R.^ad , Swerdlow, R.^ar , Tanzi, R.^bf , Trojanowski, J.^ab , Troncoso, J.^y , Tsuang, D.^bs , Valladares, O.^ab , Van Deerlin, V.^ab , Van Eldik, L.^w , Vardarajan, B.^ag , Vinters, H.^bi , Vonsattel, J.P.^ag , Wang, L.-S.^ab , Weintraub, S.^al , Welsh-Bohmer, K.^aq , Wilhelmsen, K.^ca , Williamson, J.^ag , Wingo, T.^bh , Woltjer, R.^bq , Wright, C.^aj , Wu, C.-K.^cb , Younkin, S.^an , Yu, C.-E.^ak , Yu, L.^af , Zhao, Y.^ab

^a Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, 1207 17th Ave S., Nashville, TN 37212, United States
^b Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^c Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
^d John T MacDonald Foundation, Department of Human Genetics, University of Miami, Miami, FL, United States
^e Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, United States
^f Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States
^g Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
^h Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States
ⁱ Department of Medicine, University of Washington, Seattle, United States
^j Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, United States
^k Cell Circuits Program, Broad Institute, Cambridge, MA, United States
^l Department of Epidemiology, School of Public Health, University of Washington, Seattle, United States
^m Department of Pathology, University of Washington, Seattle, United States
ⁿ Department of Pathology, Stanford University, Stanford, CA, United States
^o Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^p Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Molndal, Sweden
^q Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, Sweden
^r Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London, United Kingdom
^s UK Dementia Research Institute, London, United Kingdom
^t Kaiser Permanente Washington Health Research Institute, Seattle, United States
^u Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, United States
^v Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^w University of Kentucky, United States
^x University of Texas Southwestern Medical Center, United States
^y Johns Hopkins University, United States
^z University of Michigan, United States
^aa Indiana University, United States
^ab University of Pennsylvania Perelman School of Medicine, United States
^ac University of Wisconsin, United States
^ad Boston University, United States
^ae University of North Texas Health Science Center, United States
^af Rush University Medical Center, United States
^ag Columbia University, United States
^ah Banner Sun Health Research Institute, United States
^ai University of Pittsburgh School of Medicine, United States
^aj University of Miami, United States
^ak University of Washington, United States
^al Northwestern University Feinberg School of Medicine, United States
^am Harvard School of Public Health, United States
^an Mayo Clinic, United States
^ao Swedish Medical Center, United States
^ap University of California San Francisco, United States
^aq Duke University, United States
^ar University of Kansas Medical Center, United States
^as Mount Sinai School of Medicine, United States
^at Washington University, United States
^au University of South Florida, United States
^av Fred Hutchinson Cancer Research Center, United States
^aw University of Southern California, United States
^ax University of California Irvine, United States
^ay Washington University School of Medicine, United States
^az Brigham and Women’s Hospital, Harvard Medical School, United States
^ba University of California Davis, United States
^bb Baylor College of Medicine, United States
^bc Mount Sinai Medical Center, United States
^bd University of Alabama at Birmingham, United States
^be New York University, United States
^bf Massachusetts General Hospital, Harvard Medical School, United States
^bg University of California San Diego, United States
^bh Emory University, United States
^bi University of California Los Angeles, Harvard Medical School, United States
^bj Case Western Reserve University, United States
^bk Children’s Hospital of Philadelphia, United States
^bl University of Pittsburgh, United States
^bm University College London, United Kingdom
^bn Translational Genomics Research Institute, United States
^bo Albert Einstein College of Medicine, United States
^bp Brigham Young University, United States
^bq Oregon Health and Science University, United States
^br Cleveland Clinic, United States
^bs VA Puget Sound Health Care System, GRECC, United States
^bt University of Pittsburgh Alzheimer’s Disease Research Center, United States
^bu Pfizer Worldwide Research and Development, United States
^bv University of Washington School of Medicine, United States
^bw University of Colorado School of Medicine, United States
^bx University of Toronto, Canada
^by University of Texas Southwestern, United States
^bz South Texas Veterans Health Administration Geriatric Research Education and Clinical Center (GRECC), UT Health Science Center at San Antonio, United States
^ca University of North Carolina Chapel Hill, United States
^cb Texas Tech University Health Science Center, United States

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. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus