Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease: A Genome-Wide Association Study
Open accessAbstract
IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.
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APOE remains the only locus repeatedly associated with AAO, but PICALM and BIN1 have also been reported to affect AAO.
“To date, APOE remains the only locus repeatedly associated with AAO8,9, but PICALM and BIN1 have also been reported to affect AAO6,10,11.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [6]
Few studies have investigated the genetic basis of age at onset of AD.
“For example, few studies6,7 have investigated the genetic basis of age at onset of AD (AAO).”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [6]
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- Authors
- Naj, A. C., Jun, G., Reitz, C., Kunkle, B. W., Perry, W., Park, Y. S., Beecham, G. W., Rajbhandary, R. A., Hamilton-Nelson, K. L., Wang, L.-S., Kauwe, J. S. K., Huentelman, M. J., Myers, A. J., Bird, T. D., Boeve, B. F., Baldwin, C. T., Jarvik, G. P., Crane, P. K., Rogaeva, E., Barmada, M. M., Demirci, F. Y., Cruchaga, C., Kramer, P. L., Ertekin-Taner, N., Hardy, J., Graff-Radford, N. R., Green, R. C., Larson, E. B., St. George-Hyslop, P. H., Buxbaum, J. D., Evans, D. A., Schneider, J. A., Lunetta, K. L., Kamboh, M. I., Saykin, A. J., Reiman, E. M., De Jager, P. L., Bennett, D. A., Morris, J. C., Montine, T. J., Goate, A. M., Blacker, D., Tsuang, D. W., Hakonarson, H., Kukull, W. A., Foroud, T. M., Martin, E. R., Haines, J. L., Mayeux, R. P., Farrer, L. A., Schellenberg, G. D., Pericak-Vance, M. A., Albert, M. S., Albin, R. L., Apostolova, L. G., Arnold, S. E., Barber, R., Barnes, L. L., Beach, T. G., Becker, J. T., Beekly, D., Bigio, E. H., Bowen, J. D., Boxer, A., Burke, J. R., Cairns, N. J., Cantwell, L. B., Cao, C., Carlson, C. S., Carney, R. M., Carrasquillo, M. M., Carroll, S. L., Chui, H. C., Clark, D. G., Corneveaux, J., Cribbs, D. H., Crocco, E. A., DeCarli, C., DeKosky, S. T., Dick, M., Dickson, D. W., Duara, R., Faber, K. M., Fallon, K. B., Farlow, M. R., Ferris, S., Frosch, M. P., Galasko, D. R., Ganguli, M., Gearing, M., Geschwind, D. H., Ghetti, B., Gilbert, J. R., Glass, J. D., Growdon, J. H., Hamilton, R. L., Harrell, L. E., Head, E., Honig, L. S., Hulette, C. M., Hyman, B. T., Jicha, G. A., Jin, L.-W., Karydas, A., Kaye, J. A., Kim, R., Koo, E. H., Kowall, N. W., Kramer, J. H., LaFerla, F. M., Lah, J. J., Leverenz, J. B., Levey, A. I., Li, G., Lieberman, A. P., Lin, C.-F., Lopez, O. L., Lyketsos, C. G., Mack, W. J., Martiniuk, F., Mash, D. C., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McKee, A. C., Mesulam, M., Miller, B. L., Miller, C. A., Miller, J. W., Murrell, J. R., Olichney, J. M., Pankratz, V. S., Parisi, J. E., Paulson, H. L., Peskind, E., Petersen, R. C., Pierce, A., Poon, W. W., Potter, H., Quinn, J. F., Raj, A., Raskind, M., Reisberg, B., Ringman, J. M., Roberson, E. D., Rosen, H. J., Rosenberg, R. N., Sano, M., Schneider, L. S., Seeley, W. W., Smith, A. G., Sonnen, J. A., Spina, S., Stern, R. A., Tanzi, R. E., Thornton-Wells, T. A., Trojanowski, J. Q., Troncoso, J. C., Valladares, O., Van Deerlin, V. M., Van Eldik, L. J., Vardarajan, B. N., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Williamson, J., Wishnek, S., Woltjer, R. L., Wright, C. B., Younkin, S. G., Yu, C.-E., & Yu, L.
- Affiliations
- University of Pennsylvania (US)
- Boston University (US)
- Columbia University (US)
- University of Miami (US)
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida
- Brigham Young University (US)
- Translational Genomics Research Institute (US)
- University of Washington (US)
- Mayo Clinic (US)
- University of Toronto (CA)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- Oregon Health & Science University (US)
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida26Department of Neurology, Mayo Clinic, Jacksonville, Florida
- UCL Queen Square Institute of Neurology (GB)
- Brigham and Women's Hospital (US)
- Group Health Cooperative (US)
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada30Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, England
- Icahn School of Medicine at Mount Sinai (US)
- Rush University Medical Center (US)
- Indiana University Indianapolis (US)
- Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts44Program in Medical and Population Genetics, Broad Ins
- Harvard University (US)
- Children's Hospital of Philadelphia (US)
- Vanderbilt University (US)
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida9The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida
- Johns Hopkins University (US)
- University of Michigan (US)
- University of California, Los Angeles (US)
- University of North Texas Health Science Center (US)
- Northwestern University (US)
- University of California, San Francisco (US)
- Duke University (US)
- University of South Florida (US)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- University of Southern California (US)
- University of Alabama at Birmingham (US)
- University of California Davis Medical Center (US)
- University of Virginia (US)
- University of California, Irvine (US)
- Mount Sinai Hospital (US)
- New York University (US)
- Massachusetts General Hospital (US)
- University of California San Diego (US)
- Emory University (US)
- University of Kentucky (US)
- Columbia University Irving Medical Center (US)
- Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Fred Hutch Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
- Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington
- Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois127Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- ORCID
- Naj, Adam C.
- Jun, Gyungah
- Kunkle, Brian W.
- Beecham, Gary W.
- Huentelman, Matthew J.
- Myers, Amanda J.
- Bird, Thomas D.
- Boeve, Bradley F.
- Jarvik, Gail P.
- Crane, Paul K.
- Rogaeva, Ekaterina
- Barmada, M. Michael
- Demirci, F. Yesim
- Cruchaga, Carlos
- Hardy, John
- Green, Robert C.
- Larson, Eric B.
- Buxbaum, Joseph D.
- Evans, Denis A.
- Schneider, Julie A.
- Lunetta, Kathryn L.
- Kamboh, M. Ilyas
- Saykin, Andrew J.
- Reiman, Eric M.
- Bennett, David A.
- Morris, John C.
- Montine, Thomas J.
- Goate, Alison M.
- Blacker, Deborah
- Tsuang, Debby W.
- Hakonarson, Hakon
- Kukull, Walter A.
- Foroud, Tatiana M.
- Martin, Eden R.
- Haines, Jonathan L.
- Mayeux, Richard P.
- Farrer, Lindsay A.
- Schellenberg, Gerard D.
- Albert, Marilyn S.
- Albin, Roger L.
- Apostolova, Liana G.
- Arnold, Steven E.
- Barber, Robert
- Barnes, Lisa L.
- Beach, Thomas G.
- Becker, James T.
- Bigio, Eileen H.
- Bowen, James D.
- Boxer, Adam
- Burke, James R.
- Cairns, Nigel J.
- Cao, Chuanhai
- Carrasquillo, Minerva M.
- Carroll, Steven L.
- Chui, Helena C.
- Clark, David G.
- Cribbs, David H.
- Crocco, Elizabeth A.
- DeCarli, Charles
- DeKosky, Steven T.
- Dickson, Dennis W.
- Duara, Ranjan
- Faber, Kelley M.
- Farlow, Martin R.
- Ferris, Steven
- Frosch, Matthew P.
- Galasko, Douglas R.
- Ganguli, Mary
- Gearing, Marla
- Geschwind, Daniel H.
- Ghetti, Bernardino
- Gilbert, John R.
- Glass, Jonathan D.
- Hamilton, Ronald L.
- Head, Elizabeth
- Honig, Lawrence S.
- Hyman, Bradley T.
- Jicha, Gregory A.
- Kaye, Jeffrey A.
- Koo, Edward H.
- Kowall, Neil W.
- Kramer, Joel H.
- LaFerla, Frank M.
- Lah, James J.
- Leverenz, James B.
- Levey, Allan I.
- Li, Ge
- Lieberman, Andrew P.
- Lin, Chiao-Feng
- Lyketsos, Constantine G.
- Mack, Wendy J.
- Martiniuk, Frank
- Mash, Deborah C.
- Masliah, Eliezer
- McCurry, Susan M.
- McDavid, Andrew N.
- McKee, Ann C.
- Mesulam, Marsel
- Miller, Bruce L.
- Murrell, Jill R.
- Olichney, John M.
- Pankratz, Vernon S.
- Paulson, Henry L.
- Peskind, Elaine
- Petersen, Ronald C.
- Poon, Wayne W.
- Potter, Huntington
- Quinn, Joseph F.
- Raskind, Murray
- Reisberg, Barry
- Ringman, John M.
- Roberson, Erik D.
- Sano, Mary
- Schneider, Lon S.
- Seeley, William W.
- Smith, Amanda G.
- Sonnen, Joshua A.
- Spina, Salvatore
- Stern, Robert A.
- Tanzi, Rudolph E.
- Trojanowski, John Q.
- Troncoso, Juan C.
- Valladares, Otto
- Vardarajan, Badri N.
- Vinters, Harry V.
- Welsh-Bohmer, Kathleen A.
- Williamson, Jennifer
- Woltjer, Randall L.
- Yu, Chang-En
- Yu, Lei
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2014-11-01
- Volume
- 71
- Issue
- 11
- Pages
- 1394
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4314944
- OpenAlex
- W2029563076
- Cited by
- 185
- References
- 41
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 11 · 2023: 12 · 2022: 11 · 2021: 19 · 2020: 19 · 2019: 16 · 2018: 14 · 2017: 22 · 2016: 24 · 2015: 22 · 2014: 1
- FWCI
- 15.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs (U01 AG024904)
- Alzheimer's Association (IIRG-05–14147, IIRG-08-89720, U01 AG024904)
- Dana Foundation (K01 AG030514, U01 AG024904)
- Bristol-Myers Squibb (U01 AG024904, AG024904)
- Eli Lilly and Company (U01 AG024904, AG024904)
- Pfizer (AG024904, U01 AG024904)
- AstraZeneca
- GlaxoSmithKline
- Novartis
- Brigham and Women's Hospital
- Massachusetts General Hospital
- Office of Research and Development
- Children's Hospital of Philadelphia
- Vanderbilt University
- F. Hoffmann-La Roche (AG024904, U01 AG024904)
- Medpace (U01 AG024904)
- Synarc (U01 AG024904, K01 AG030514)
- Washington University in St. Louis
- Alzheimer's Disease Neuroimaging Initiative (U01AG024904, AG024904, K01 AG030514)
- University of Washington
- University of Pittsburgh
- Rush University
- Northern California Institute for Research and Education (U01 AG024904, K01 AG030514)
- Wellcome Trust (100140, 089703, 081864)
- Broad Institute
- Alzheimer's Research Trust
- Parkinson's UK (G-0907)
- Newcastle University
- Stichting MS Research
- Elan (U01 AG024904)
- Eisai (U01 AG024904, AG024904)
- Universitat de Barcelona
- Hersenstichting
- FONDATION ALZHEIMER
- National Institutes of Health (5rc2ag036502-02, UL1TR001108, UL1TR000135, 5r01ag027944-05, 5u01ag024904-10, 7r01ag019757-06, 5r37ag015473-15)
- Genentech (AG024904, U01 AG024904)
- Canadian Institutes of Health Research
- Medical Research Council (U01 AG024904, K01 AG030514)
- National Institute on Aging (U01-AG-024904, R01AG017917, P01AG010491, P50 AG016575, AG05 128, P30AG010129, P30AG010133, R01AG019085, P30 AG 08051, P50AG005144, U01‐AG10483, R01AG33193, P50 AG016576, R01AG030146, AG021547, R01 AG30146, AG036535, AG010491, R01‐AG17917, U24 AG026390, P30AG028383, R01 AG15819, P30AG012300, R01AG041718, AG 025688, P50AG016577, P50AG005133, R01-AG027944, AG 024904, AG-034504, P30AG028377, U01AG006781, U01AG016976, P50AG005131, R01-AG019757, R01AG034504, R37-AG015473, P50AG005138, R01AG026390, AG041718, R01AG022374, P50AG016570, K01AG030514, P50AG005128, P30AG010124, P50AG016573, AG019757, R01AG021547, R01AG041232, R01AG030653, U01AG010483, R01AG015819, P30AG008017, P30AG010161, U01AG032984, R01AG012101, R01AG031581, P30AG008051, R01AG041797, RC2-AG036502, P50AG016582, P50AG008702, P50AG005681, P50AG005142, P50AG008671, P30AG019610, R01AG026916, P50AG005146, P01 AG0 3991, P01AG003991, 1RC2AG036502, U24AG026395, P30AG013846, P50AG005136, P50AG005134, RC2AG036535, P30AG013854, R01AG025259, P50AG025688, R01AG017173, RC2AG036528, R01AG033193, P01AG002219, RF1AG015819, R01AG013616, P30 AG-10133, U24AG056270, P01AG019724, U19AG024904, U24AG021886, P30AG062421, P50AG023501, AG027944, R01AG020688, AG 030653, P50AG016574, R01AG035137, UO1-AG06781)
- National Institute of Mental Health (MH60451, R01MH080295, P50MH060451)
- National Human Genome Research Institute (HG004610, U01HG004610)
- National Cancer Institute (R01CA129769, U54CA137788, U54CA132378)
- National Institute of Neurological Disorders and Stroke (NS3 9764, R01NS080820, R01NS059873, P50NS039764)
- National Institute of Environmental Health Sciences (P30ES013508)
- National Institute of Biomedical Imaging and Bioengineering (U01 AG024904, AG024904)
- National Center for Research Resources (MO1 RR000-96, UL1RR02777, UL1RR029893, M01RR000096)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- late-onset Alzheimer's disease, age of onset, apolipoprotein E, complement receptor 1, BIN1, PICALM, cumulative genetic risk, single nucleotide polymorphisms, disease onset timing, genetic risk variants
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Genotype, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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