Genetically elevated high‐density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

• Main Authors: Gina M. Peloso, Sven J. van derLee, International Genomics of Alzheimer's Project (IGAP), R. Sims, S.J. van derLee, A.C. Naj, C. Bellenguez, N. Badarinarayan, J. Jakobsdottir, B.W. Kunkle, A. Boland, R. Raybould, J.C. Bis, E.R. Martin, B. Grenier‐Boley, S. Heilmann‐Heimbach, V. Chouraki, A.B. Kuzma, K. Sleegers, M. Vronskaya, A. Ruiz, R.R. Graham, R. Olaso, P. Hoffmann, M.L. Grove, B.N. Vardarajan, M. Hiltunen, M.M. Nöthen, C.C. White, K.L. Hamilton‐Nelson, J. Epelbaum, W. Maier, S.H. Choi, G.W. Beecham, C. Dulary, S. Herms, A.V. Smith, C.C. Funk, Derbois, A.J. Forstner, S. Ahmad, H. Li, D. Bacq, D. Harold, C.L. Satizabal, O. Valladares, A. Squassina, R. Thomas, J.A. Brody, L. Qu, P. Sánchez‐Juan, T. Morgan, F.J. Wolters, Y. Zhao, F.S. Garcia, N. Denning, M. Fornage, J. Malamon, M.C.D. Naranjo, E. Majounie, T.H. Mosley, B. Dombroski, D. Wallon, M.K. Lupton, J. Dupuis, P. Whitehead, L. Fratiglioni, C. Medway, X. Jian, S. Mukherjee, L. Keller, K. Brown, H. Lin, L.B. Cantwell, F. Panza, B. McGuinness, S. Moreno‐Grau, J.D. Burgess, V. Solfrizzi, P. Proitsi, H.H. Adams, M. Allen, D. Seripa, P. Pastor, L.A. Cupples, N.D. Price, D. Hannequin, A. Frank‐García, D. Levy, P. Chakrabarty, P. Caffarra, I. Giegling, A.S. Beiser, V. Giedraitis, H. Hampel, M.E. Garcia, X. Wang, L. Lannfelt, P. Mecocci, G. Eiriksdottir, P.K. Crane, F. Pasquier, V. Boccardi, I. Henández, R.C. Barber, M. Scherer, L. Tarraga, P.M. Adams, M. Leber, Y. Chen, M.S. Albert, S. Riedel‐Heller, V. Emilsson, D. Beekly, A. Braae, R. Schmidt, D. Blacker, C. Masullo, H. Schmidt, R.S. Doody, G. Spalletta, W.T. Longstreth Jr., T.J. Fairchild, P. Bossù, O.L. Lopez, M.P. Frosch, E. Sacchinelli, B. Ghetti, Q. Yang, R.M. Huebinger, F. Jessen, S. Li, M.I. Kamboh, J. Morris, O. Sotolongo‐Grau, M.J. Katz, C. Corcoran, M. Dunstan, A. Braddel, C. Thomas, A. Meggy, R. Marshall, A. Gerrish, J. Chapman, M. Aguilar, S. Taylor, M. Hill, M.D. Fairén, A. Hodges, B. Vellas, H. Soininen, I. Kloszewska, M. Daniilidou, J. Uphill, Y. Patel, J.T. Hughes, J. Lord, J. Turton, A.M. Hartmann, R. Cecchetti, C. Fenoglio, M. Serpente, M. Arcaro, C. Caltagirone, M.D. Orfei, A. Ciaramella, S. Pichler, M. Mayhaus, W. Gu, A. Lleó, J. Fortea, R. Blesa, I.S. Barber, K. Brookes, C. Cupidi, R.G. Maletta, D. Carrell, S. Sorbi, S. Moebus, M. Urbano, A. Pilotto, J. Kornhuber, P. Bosco, S. Todd, D. Craig, J. Johnston, M. Gill, B. Lawlor, A. Lynch, N.C. Fox, J. Hardy, ARUK Consortium, R.L. Albin, L.G. Apostolova, S.E. Arnold, S. Asthana, C.S. Atwood, C.T. Baldwin, L.L. Barnes, S. Barral, T.G. Beach, J.T. Becker, E.H. Bigio, T.D. Bird, B.F. Boeve, J.D. Bowen, A. Boxer, J.R. Burke, J.M. Burns, J.D. Buxbaum, N.J. Cairns, C. Cao, C.S. Carlson, C.M. Carlsson, R.M. Carney, M.M. Carrasquillo, S.L. Carroll, C.C. Diaz, H.C. Chui, D.G. Clark, D.H. Cribbs, E.A. Crocco, C. DeCarli, M. Dick, R. Duara, D.A. Evans, K.M. Faber, K.B. Fallon, D.W. Fardo, M.R. Farlow, S. Ferris, T.M. Foroud, D.R. Galasko, M. Gearing, D.H. Geschwind, J.R. Gilbert, N.R. Graff‐Radford, R.C. Green, J.H. Growdon, R.L. Hamilton, L.E. Harrell, L.S. Honig, M.J. Huentelman, C.M. Hulette, B.T. Hyman, G.P. Jarvik, E. Abner, L.W. Jin, G. Jun, A. Karydas, J.A. Kaye, R. Kim, N.W. Kowall, J.H. Kramer, F.M. LaFerla, J.J. Lah, J.B. Leverenz, A.I. Levey, G. Li, A.P. Lieberman, K.L. Lunetta, C.G. Lyketsos, D.C. Marson, F. Martiniuk, D.C. Mash, E. Masliah, W.C. McCormick, S.M. McCurry, A.N. McDavid, A.C. McKee, M. Mesulam, B.L. Miller, C.A. Miller, J.W. Miller, J.C. Morris, J.R. Murrell, A.J. Myers, S. O'Bryant, J.M. Olichney, V.S. Pankratz, J.E. Parisi, H.L. Paulson, W. Perry, E. Peskind, A. Pierce, W.W. Poon, H. Potter, J.F. Quinn, A. Raj, M. Raskind, B. Reisberg, C. Reitz, J.M. Ringman, E.D. Roberson, E. Rogaeva, H.J. Rosen, R.N. Rosenberg, M.A. Sager, A.J. Saykin, J.A. Schneider, L.S. Schneider, W.W. Seeley, A.G. Smith, J.A. Sonnen, S. Spina, R.A. Stern, R.H. Swerdlow, R.E. Tanzi, T.A. Thornton‐Wells, J.Q. Trojanowski, J.C. Troncoso, V.M. Van Deerlin, L.J. Van Eldik, H.V. Vinters, J.P. Vonsattel, S. Weintraub, K.A. Welsh‐Bohmer, K.C. Wilhelmsen, J. Williamson, T.S. Wingo, R.L. Woltjer, C.B. Wright, C.E. Yu, L. Yu, F. Garzia, F. Golamaully, G. Septier, S. Engelborghs, R. Vandenberghe, P.P. De Deyn, C.M. Fernadez, Y.A. Benito, H. Thonberg, C. Forsell, L. Lilius, A. Kinhult‐Stählbom, L. Kilander, R. Brundin, L. Concari, S. Helisalmi, A.M. Koivisto, A. Haapasalo, V. Dermecourt, N. Fievet, O. Hanon, C. Dufouil, A. Brice, K. Ritchie, B. Dubois, J.J. Himali, C.D. Keene, J. Tschanz, A.L. Fitzpatrick, W.A. Kukull, M. Norton, T. Aspelund, E.B. Larson, R. Munger, J.I. Rotter, R.B. Lipton, M.J. Bullido, A. Hofman, T.J. Montine, E. Coto, E. Boerwinkle, R.C. Petersen, V. Alvarez, F. Rivadeneira, E.M. Reiman, M. Gallo, C.J. O'Donnell, J.S. Reisch, A.C. Bruni, D.R. Royall, M. Dichgans, M. Sano, D. Galimberti, P. St George‐Hyslop, E. Scarpini, D.W. Tsuang, M. Mancuso, U. Bonuccelli, A.R. Winslow, A. Daniele, C.K. Wu, GERAD/PERADES, CHARGE, ADGC, EADI, O. Peters, B. Nacmias, M. Riemenschneider, R. Heun, C. Brayne, D.C. Rubinsztein, J. Bras, R. Guerreiro, A. Al‐Chalabi, C.E. Shaw, J. Collinge, D. Mann, M. Tsolaki, J. Clarimón, R. Sussams, S. Lovestone, M.C. O'Donovan, M.J. Owen, T.W. Behrens, S. Mead, A.M. Goate, A.G. Uitterlinden, C. Holmes, C. Cruchaga, M. Ingelsson, D.A. Bennett, J. Powell, T.E. Golde, C. Graff, P.L. De Jager, K. Morgan, N. Ertekin‐Taner, O. Combarros, B.M. Psaty, P. Passmore, S.G. Younkin, C. Berr, V. Gudnason, D. Rujescu, D.W. Dickson, J.F. Dartigues, A.L. DeStefano, S. Ortega‐Cubero, H. Hakonarson, D. Campion, M. Boada, J.K. Kauwe, L.A. Farrer, C. Van Broeckhoven, M.A. Ikram, L. Jones, J.L. Haines, C. Tzourio, L.J. Launer, V. Escott‐Price, R. Mayeux, J.F. Deleuze, N. Amin, P.A. Holmans, M.A. Pericak‐Vance, P. Amouyel, C.M. vanDuijn, A. Ramirez, L.S. Wang, J.C. Lambert, S. Seshadri, J. Williams, G.D. Schellenberg, Anita L. Destefano, Sudha Seshardi
• Format: Article
• Language: English
• Published: Wiley 2018-01-01
• Series: Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring
• Subjects: Genetics; HDL‐C; Single nucleotide polymorphisms; Instrumental variables; Cholesteryl ester transfer protein
• Online Access: https://doi.org/10.1016/j.dadm.2018.08.008

Abstract Introduction There is conflicting evidence whether high‐density lipoprotein cholesterol (HDL‐C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL‐C. We aimed to assess AD risk by genetically predicted HDL‐C. Methods Ten single nucleotide polymorphisms within the CETP locus predicting HDL‐C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR‐Egger. Results Based on 10 single nucleotide polymorphisms distinctly predicting HDL‐C in the CETP locus, we found that HDL‐C was not associated with risk of AD (P > .7). Discussion Our study does not support the role of HDL‐C on risk of AD through HDL‐C altered by CETP. This study does not rule out other mechanisms by which HDL‐C affects risk of AD.