Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
Authors: Reiman Eric M. , Arboleda-Velasquez Joseph F. , Quiroz Yakeel T. , Huentelman Matthew J. , Beach Thomas G. , Caselli Richard J. , Chen Yinghua , Su Yi , Myers Amanda J. , Hardy John , Paul Vonsattel Jean , Younkin Steven G. , Bennett David A. , De Jager Philip L. , Larson Eric B. , Crane Paul K. , Keene C. Dirk , Kamboh M. Ilyas , Kofler Julia K. , Duque Linda , Gilbert John R. , Gwirtsman Harry E. , Buxbaum Joseph D. , Dickson Dennis W. , Frosch Matthew P. , Ghetti Bernardino F. , Lunetta Kathryn L. , Wang Li-San , Hyman Bradley T. , Kukull Walter A. , Foroud Tatiana , Haines Jonathan L. , Mayeux Richard P. , Pericak-Vance Margaret A. , Schneider Julie A. , Trojanowski John Q. , Farrer Lindsay A. , Schellenberg Gerard D. , Beecham Gary W. , Montine Thomas J. , Jun Gyungah R. ,   The Alzheimer’s Disease Genetics Consortium, Abner Erin , Adams Perrie M. , Albert Marilyn S. , Albin Roger L. , Apostolova Liana G. , Arnold Steven E. , Asthana Sanjay , Atwood Craig S. , Baldwin Clinton T. , Barber Robert C. , Barnes Lisa L. , Barral Sandra , Becker James T. , Beekly Duane , Bigio Eileen H. , Bird Thomas D. , Blacker Deborah , Boeve Bradley F. , Bowen James D. , Boxer Adam , Burke James R. , Burns Jeffrey M. , Cairns Nigel J. , Cantwell Laura B. , Cao Chuanhai , Carlson Chris S. , Carlsson Cynthia M. , Carney Regina M. , Carrasquillo Minerva M. , Chui Helena C. , Cribbs David H. , Crocco Elizabeth A. , Cruchaga Carlos , DeCarli Charles , Dick Malcolm , Doody Rachelle S. , Duara Ranjan , Ertekin-Taner Nilufer , Evans Denis A. , Faber Kelley M. , Fairchild Thomas J. , Fallon Kenneth B. , Fardo David W. , Farlow Martin R. , Ferris Steven , Galasko Douglas R. , Gearing Marla , Geschwind Daniel H. , Ghisays Valentina , Goate Alison M. , Graff-Radford Neill R. , Green Robert C. , Growdon John H. , Hakonarson Hakon , Hamilton Ronald L. , Hamilton-Nelson Kara L. , Harrell Lindy E. , Honig Lawrence S. , Huebinger Ryan M. , Hulette Christine M. , Jarvik Gail P. , Jin Lee-Way , Karydas Anna , Katz Mindy J. , Kauwe John S. K. , Kaye Jeffrey A. , Kim Ronald , Kowall Neil W. , Kramer Joel H. , Kunkle Brian W. , Kuzma Amanda P. , LaFerla Frank M. , Lah James J. , Leung Yuk Ye , Leverenz James B. , Levey Allan I. , Li Ge , Lieberman Andrew P. , Lipton Richard B. , Lopez Oscar L. , Lyketsos Constantine G. , Malamon John , Marson Daniel C. , Martin Eden R. , Martiniuk Frank , Mash Deborah C. , Masliah Eliezer , McCormick Wayne C. , McCurry Susan M. , McDavid Andrew N. , McDonough Stefan , McKee Ann C. , Mesulam Marsel , Miller Bruce L. , Miller Carol A. , Miller Joshua W. , Morris John C. , Mukherjee Shubhabrata , Naj Adam C. , O’Bryant Sid , Olichney John M. , Parisi Joseph E. , Paulson Henry L. , Peskind Elaine , Petersen Ronald C. , Pierce Aimee , Poon Wayne W. , Potter Huntington , Qu Liming , Quinn Joseph F. , Raj Ashok , Raskind Murray , Reisberg Barry , Reisch Joan S. , Reitz Christiane , Ringman John M. , Roberson Erik D. , Rogaeva Ekaterina , Rosen Howard J. , Rosenberg Roger N. , Royall Donald R. , Sager Mark A. , Sano Mary , Saykin Andrew J. , Schneider Lon S. , Seeley William W. , Smith Amanda G. , Sonnen Joshua A. , Spina Salvatore , George-Hyslop Peter St , Stern Robert A. , Swerdlow Russell H. , Tanzi Rudolph E. , Troncoso Juan C. , Tsuang Debby W. , Valladares Otto , Van Deerlin Vivianna M. , Van Eldik Linda J. , Vardarajan Badri N. , Vinters Harry V. , Weintraub Sandra , Welsh-Bohmer Kathleen A. , Wilhelmsen Kirk C. , Williamson Jennifer , Wingo Thomas S. , Woltjer Randall L. , Wright Clinton B. , Wu Chuang-Kuo , Yu Chang-En , Yu Lei , Zhao Yi 
Published: February 2020

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.