Accepted for Publication: June 23, 2014.
Published Online: December 22, 2014. doi:10.1001/jamaneurol.2014.2157.
Study concept and design: Wang, Naj, Cruchaga, Zetterberg, Blennow, Kauwe, Haines, Farrer, Pericak-Vance, Mayeux, Schellenberg.
Acquisition, analysis, or interpretation of data: Wang, Naj, Graham, Crane, Kunkle, Cruchaga, Gonzalez Murcia, Cannon-Albright, Baldwin, Zetterberg, Blennow, Kukull, Faber, Schupf, Norton, Tschanz, Munger, Corcoran, Rogaeva, Albert, Albin, Apostolova, Arnold, Barber, Barmada, Barnes, Beach, Becker, Beecham, Beekly, Bennett, Bigio, Bird, Blacker, Boeve, Bowen, Boxer, Burke, Buxbaum, Cairns, Cao, Carlson, Carroll, Chui, Clark, Cribbs, Crocco, DeCarli, DeKosky, Demirci, Dick, Dickson, Duara, Ertekin-Taner, Fallon, Farlow, Ferris, Frosch, Galasko, Ganguli, Gearing, Geschwind, Ghetti, Gilbert, Glass, Graff-Radford, Growdon, Hamilton, Hamilton-Nelson, Harrell, Head, Honig, Hulette, Hyman, Jarvik, Jicha, Jin, Jun, Kamboh, Karydas, Kaye, Kim, Koo, Kowall, J. H. Kramer, P. Kramer, LaFerla, Lah, Leverenz, Levey, Li, Lieberman, Lopez, Lunetta, Lyketsos, Mack, Marson, Martin, Martiniuk, Mash, Masliah, McCormick, McCurry, McDavid, McKee, Mesulam, B. L. Miller, C. A. Miller, J. W. Miller, Montine, Morris, Murrell, Olichney, Parisi, Perry, Peskind, Petersen, Pierce, Poon, Potter, Quinn, Raj, Raskind, Reiman, Reisberg, Reitz, Ringman, Roberson, Rosen, Rosenberg, Sano, Saykin, J. A. Schneider, L. S. Schneider, Seeley, Smith, Sonnen, Spina, Stern, Tanzi, Thornton-Wells, Trojanowski, Troncoso, Tsuang, Van Deerlin, Van Eldik, Vardarajan, Vinters, Vonsattel, Weintraub, Welsh-Bohmer, Williamson, Wishnek, Woltjer, Wright, Younkin, C.-E. Yu, L. Yu, Lin, Dombroski, Cantwell, Partch, Valladares, Hakonarson, St George-Hyslop, Green, Goate, Foroud, Carney, Larson, Behrens, Kauwe, Pericak-Vance, Mayeux, Schellenberg.
Drafting of the manuscript: Wang, Naj, Schellenberg.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Wang, Naj, Gonzalez Murcia, Corcoran, Carlson, Ghetti, Hamilton-Nelson, Jun, Van Deerlin, Foroud, Kauwe, Haines, Schellenberg.
Obtained funding: Munger, Barnes, Bennett, DeKosky, Galasko, Ganguli, Ghetti, Jarvik, Kamboh, Lopez, Mesulam, Montine, Morris, Reiman, Saykin, Hakonarson, St George-Hyslop, Larson, Haines, Farrer, Mayeux, Schellenberg.
Administrative, technical, or material support: Naj, Cruchaga, Zetterberg, Blennow, Norton, Munger, Arnold, Beach, Becker, Beekly, Bennett, Boeve, Cairns, Cao, Chui, Cribbs, DeKosky, Ertekin-Taner, Ferris, Geschwind, Ghetti, Hamilton, Harrell, Hyman, Jarvik, Jin, LaFerla, Lieberman, Mash, McCormick, Parisi, Potter, Rosen, Sano, Trojanowski, Vonsattel, Larson, Behrens, Kauwe, Schellenberg.
Study supervision: Munger, Leverenz, Hakonarson, Pericak-Vance, Mayeux, Schellenberg.
Conflict of Interest Disclosures: Drs Graham and Behrens are full-time employees of Genentech, Inc. Dr DeKosky is a consultant for AstraZeneca, Eli Lilly and Co, Merck and Co, and Rivermend and is involved in clinical trials with Baxter, Elan, Janssen, Novartis, and Pfizer. Dr Farlow receives research support from Accera, Biogen, Eisai, Eli Lilly and Co, Genentech, MedAvante/AstraZeneca, and Navidea; is on the speaker’s bureau at Eisai, Pfizer, Forest, Novartis, and Eli Lilly and Co; and is a consultant or advisory board member for Accera, Alltech, Avanir, Eisai, Med Res, Hilicon, Medavante, Medivation, Merck and Co, Novartis, Pfizer, Prana Biotech, QR Pharma, Roche, Sanofi-Aventis, Schering-Plough, Toyama Pharm, Eli Lilly and Co, and UCB Pharma. Dr Ghetti has consulted for Piramal Imaging. Dr Rosenberg is the JAMA Neurology Editor and Dr Honig is the JAMA Neurology Web Editorbut neither was involved in the review process or the acceptance of the manuscript. Dr Leverenz is a consultant for Boehringer-Ingelheim, Navidea Biopharmaceuticals, and Piramal Healthcare. Dr Petersen is chair for the data monitoring committee for Pfizer and Janssen Alzheimer Immunotherapy and is a consultant for GE Healthcare and Roche. Dr Wright receives royalties from UpToDate for 2 chapters; has done legal consulting for the law firms of Abali, Milne, and Faegre Baker Daniels; is a consultant for Merck and Co; and does stroke adjudication for a National Institutes of Health clinical trial. No other disclosures were reported.
Funding/Support: The National Institute on Aging supported this work through the following grants: U01 AG032984 and RC2 AG036528 (Alzheimer’s Disease Genetics Consortium); U01 AG016976 (National Alzheimer’s Coordinating Center); U24 AG021886 (National Cell Repository for Alzheimer’s Disease); U24 AG026395, R01 AG041797, and U24 AG026390 (National Institute on Aging–Late-Onset Alzheimer’s Disease); P30 AG019610 (Banner Sun Health Research Institute); P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, and R01 MH080295 (Boston University); P50 AG008702 (Columbia University); P30 AG028377 (Duke University); AG025688 (Emory University); P30 AG10133 (Indiana University); P50 AG005146 (Johns Hopkins University); P50 AG005134 (Massachusetts General Hospital); P50 AG016574 (Mayo Clinic); P50 AG005138 (Mount Sinai School of Medicine); P30 AG08051, U01 AG16976, MO1 RR00096, and UL1 RR029893 (New York University); P30 AG013854 (Northwestern University); P30 AG008017 (Oregon Health & Science University); P30 AG010161 (Rush University); P50 AG016582 and UL1 RR02777 (Center for Clinical and Translational Science, University of Alabama at Birmingham); P30 AG010129 (University of California, Davis); P50 AG016573, P50 AG016574, P50 AG016575, P50 AG016576, and P50 AG016577 (University of California, Irvine); P50 AG016570 (University of California, Los Angeles); P50 AG005131 (University of California, San Diego); P50 AG023501 and P01 AG019724 (University of California, San Francisco); P30 AG028383 (University of Kentucky); P50 AG008671 (University of Michigan); P30 AG010124 (University of Pennsylvania); P50 AG005133 (University of Pittsburgh); P50 AG005142 (University of Southern California); P30 AG012300 (University of Texas Southwestern Medical Center); P50 AG005136 and R01 AG007584 (University of Washington); and P50 AG005681 and P01 AG03991 (Washington University). The Alzheimer’s Disease Genetics Consortium is also supported by a grant from a private foundation wishing to remain anonymous. The work completed by Boston University is also supported by grant IIRG-08-89720 from the Alzheimer’s Association and by the VA New England Geriatric Research Education and Clinical Center. The work by Miami University is also supported by grant R01 AG027944 from the National Institute on Aging and by the Alzheimer’s Association. This project was also made possible by the many contributions of individual study data sets, supported in part by the National Institutes of Health, including Adult Changes in Thought and Electronic Medical Records and Genetics (eMERGE) (grants U01 AG06781, U01 HG004610, and U01 HG006375 from the National Human Genome Research Institute), Columbia University Washington Heights–Inwood Columbia Aging Project (R01 AG037212 from the National Institutes of Health), and MIRAGE (R01 AG009029 from the National Institute on Aging). The University of Miami/Vanderbilt University/Mount Sinai School of Medicine work was supported by grants AG010491, AG002219, AG005138, AG027944, AG021547, AG019757, and R01 AG027944 from the National Institute on Aging and IIRG-05-14147 from the Alzheimer’s Association. A subset of these participants was ascertained while Dr Pericak-Vance was a faculty member at Duke University. Clinical data and genotyping efforts for the Religious Orders Study and the Memory and Aging Project were supported by grants P30 AG10161, R01 AG15819, R01 AG17917, and R01 AG30146 from the National Institute on Aging and by the Illinois Department of Public Health and the Translational Genomics Research Institute. Data and samples from the National Institute on Aging–Late-Onset Alzheimer’s Disease Family Study, which receives government support under cooperative agreement grant U24AG026390 from the National Institute on Aging, were used in this study. Data from the Cache County Study on Memory Health and Aging were supported by grants R01 AG042611 from the National Institute on Aging and MNIRG-11-205368 from the Alzheimer’s Association and by the Brigham Young University Gerontology Program and the Charleston Conference on Alzheimer’s Disease to Brigham Young University; they were also supported by grants R01 AG11380, R01 AG21136, and R01AG3272 from the National Institutes of Health and by the Utah Science, Technology, and Research Initiative and the Utah State University Agricultural Experiment Station to Utah State University. Samples from the National Cell Repository for Alzheimer’s Disease, which receives government support under cooperative agreement grant U24 AG21886 from the National Institute on Aging, were used in this study. Dr St George-Hyslop is supported by the Wellcome Trust, Howard Hughes Medical Institute, and Canadian Institute of Health Research. Drs Barmada, Demirci, and Kamboh are supported by grant AG030653 from the National Institute on Aging. Dr Wright is supported by grants K02 NS 059729 from the National Institute of Neurological Disorders and Stroke, R01 HL 108623 from the National Heart, Lung, and Blood Institute, and SDG 0735387N from the American Heart Association.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: The National Institute on Aging–Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study investigators include the following: Boston University, Boston, Massachusetts: Robert C. Green, MD, MPH, Neil W. Kowall, MD, Lindsay A. Farrer, PhD; Columbia University, New York, New York: Jennifer Williamson, MS, MPH, Vincent Santana, MBA; Duke University, Durham, North Carolina: Donald Schmechel, MD, Perry Gaskell, BS, Kathleen A. Welsh-Bohmer, PhD; Indiana University, Indianapolis: Bernardino Ghetti, MD, Martin R. Farlow, MD, Kelly Horner; Massachusetts General Hospital, Boston: John H. Growdon, MD, Deborah Blacker, MD, ScD, Rudolph E. Tanzi, PhD, Bradley T. Hyman, MD, PhD; Mayo Clinic, Rochester, Minnesota: Bradley F. Boeve, MD, Karen Kuntz, RN, Lindsay Norgaard, BS, Nathan Larson, BS; Mayo Clinic, Jacksonville, Florida: Dana Kistler, BSH, Francine Parfitt, MS, Jenny Haddow, BS; Mount Sinai School of Medicine, New York, New York: Jeremy Silverman, PhD, Michal Schnaider Beeri, PhD, Mary Sano, PhD, Joy Wang, BA, Rachel Lally, BA; Northwestern University, Chicago, Illinois: Nancy Johnson, PhD, M. Marsel Mesulam, MD, Sandra Weintraub, PhD, Eileen H. Bigio, MD; Oregon Health & Science University, Portland: Jeffery A. Kaye, MD, Patricia Kramer, PhD, Jessica Payne-Murphy, BA; Rush University, Chicago, Illinois: David A. Bennett, MD, Holli Jacobs, BA, Jeen-Soo Chang, MD, Danielle Arends, RN; University of Alabama at Birmingham, Birmingham: Lindy E. Harrell, MD, PhD; University of California, Los Angeles: George Bartzokis, MD, Jeffery Cummings, MD, Po H. Lu, PsyD, Usha Toland, MS; University of Kentucky, Lexington: William Markesbery, MD, Charles Smith, MD, Alise Brickhouse, BA; University of Pennsylvania, Philadelphia: Gerard D. Schellenberg, PhD, John Q. Trojanowski, MD, PhD, Vivianna M. Van Deerlin, MD, PhD, Elisabeth McCarty Wood, MS; University of Pittsburgh, Pittsburgh, Pennsylvania: Steven T. DeKosky, MD, Robert Sweet, MD, Elise Weamer, MPH; University of Southern California, Los Angeles: Helena C. Chui, MD, Arousiak Varpetian, MD; University of Texas Southwestern Medical Center, Dallas: Ramon Diaz-Arrastia, MD, PhD, Roger N. Rosenberg, MD, Barbara Davis, MA; University of Washington, Seattle: Thomas D. Bird, MD, Malia Rumbaugh, MS, Murray Raskind, MD; Washington University, St Louis, Missouri: Alison M. Goate, DPhil, John C. Morris, MD, Joanne Norton, MSN, RN, Denise Levitch, RN, Betsy Grant, MSW, PhD, Mary Coats, MSN, RN.
Additional Contributions: Annette Lee, PhD, and Peter K. Gregersen, MD, Feinstein Institute for Medical Research, Manhasset, New York, provided genotyping services. Creighton Phelps, PhD, Stephen Snyder, PhD, and Marilyn Miller, PhD, National Institute on Aging, Bethesda, Maryland, helped in acquiring samples and data and are ex officio members of the Alzheimer’s Disease Genetics Consortium. Duke University acknowledges John Ervin, BA, from the Brain Bank and Kathleen Hayden, PhD, in the Clinical Core for their respective efforts in the DNA and data pulls required. These individuals received no compensation from the funders for their contributions. We thank the contributors, including the Alzheimer’s Disease Centers who collected samples used in this study, as well as the patients and their families, whose help and participation made this work possible.