Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
Eric M. Reiman, Joseph F. Arboleda‐Velásquez, Yakeel T. Quiroz, Matthew J. Huentelman, Thomas G. Beach, Richard J. Caselli, Yinghua Chen, Yi Su, Amanda Myers, John Hardy, Jean Paul Vonsattel, Steven G. Younkin, David Bennett, Philip L. De Jager, Eric B. Larson, Paul K. Crane, C. Dirk Keene, M. Ilyas Kamboh, Julia Kofler, Linda Duque, John R. Gilbert, Harry E. Gwirtsman, Joseph D. Buxbaum, Dennis W. Dickson, Matthew P. Frosch, Bernardino Ghetti, Kathryn L. Lunetta, Li-San Wang, Bradley T. Hyman, Walter A. Kukull, Tatiana M. Foroud, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak‐Vance, Julie A. Schneider, John Q. Trojanowski, Lindsay A. Farrer, Gerard D. Schellenberg, Gary W. Beecham, Thomas J. Montine, Gyungah Jun, Erin L. Abner, Perrie M. Adams, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig Atwood, Clinton T. Baldwin, Robert C. Barber, Lisa L. Barnes, Sandra Barral, James T. Becker, Duane Beekly, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Jeffrey M. Burns, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Chris Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Helena C. Chui, David H. Cribbs, Elizabeth Crocco, Carlos Cruchaga, Charles DeCarli, Malcolm Dick, Rachelle S. Doody, Ranjan Duara, Nilüfer Ertekin‐Taner, Denis A. Evans, Kelley Faber, Thomas Fairchild, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Steven H. Ferris, Douglas Galasko, Marla Gearing, Daniel H. Geschwind, Valentina Ghisays, Alison Goate, Neill R. Graff‐Radford, Robert C. Green, John H. Growdon, Håkon Håkonarson, Ronald L. Hamilton, Kara L. Hamilton‐Nelson, Lindy E. Harrell, Lawrence S. Honig, Ryan M. Huebinger
Abstract
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.