Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study

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 ratio 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.

Eric M. Reiman, Eiran Abner, Perrie M Adams, Marilyn S Albright, Roger L Alban, Liana A Golde, E Arnold, Sanjay A Thacker, Craig S Atwood, Justin T Baldwin, Robert C Barber, Lisa L Barnes, Sandra Barral, James D Beekly, Eileen H Bigio, Thomas D Bird, Deborah Blacker, Bradley E Boeve, James D Bowen, Adam Boxer, James R Burke, Jeffrey M Burns, Nigel J Cairns, Daniel W Geschwind, Valentine Ghisays, Alison L Goate, Neil R Graff-Radford, Robert C Green, John H Growdon, Hakon Hakonarson, Ronald L Hamilton, Kara L Hamilton-Nelson, Lindy E Harrell, Lawrence S Honig, Ryan M Huebinger, Christine M Hulette, Gal J Parvik, Lee-Way Jin, Anna Karydas, Mindi J Katz, John S.K Kauwe, Jeffrey A Kaye, Ronald Kim, Neil W Kowal, Joel H Kramer, Brian W Kunkle, Amanda P Kuzma, Frank M LaFerla, James L Lah, Yuk Ye Leung, James B Leverenz, Allan I Levey, Andrew R Lieberman, Richard B Lipton, Oscar L Lopez, Constantine G Lyketsos, John Malamon, Daniel C Marson, Eden R Martin, Frank Martinuik, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Stephen McDonough, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Shubharat Mukherjee, Adam C Naj, Sid O’Bryant, John M Olichney, Joseph E Paris, Henry L Paulson, Elaine Pecinski, Ronald C Petersen, Aimee Pierce, Wayne W Poon, Huntington Potter, Limming Qu, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Joan S Reisch, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Donald R Royall, Mark A Sager, Mary Sano, Andrew J Saykin, Luan S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonne, Salvatore Spina, Peter St George-Hyslop, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Juan C Troncoso, Debby W Tsang, Otto Valladres, Vivianna M Van Deerlin, Linda J Van Eldik, Badri N Vardarajan, Harry V Vinters, Sandra Weintraub, Kathleen A Welsh-Bohmer, Kirk C Wilhelmsen, Jennifer Williamson, Thomas S Wingo, Randall L Woltjer, Clinton B Wright, Chuang-Kuo Wu, Cheng-En Yu, Lei Yu, Yi Zhao