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

Eric M Reiman; Joseph F Arboleda-Velasquez; Yakeel T Quiroz; Matthew J Huentelman; Thomas G Beach; Richard J Caselli; Yinghua Chen; Yi Su; Amanda J Myers; John Hardy; Jean Paul Vonsattel; Steven G Younkin; David A Bennett; Philip L De Jager; Eric B Larson; Paul K Crane; C Dirk Keene; M Ilyas Kamboh; Julia K Kofler; Linda Duque; John R Gilbert; Harry E Gwirtsman; Joseph D Buxbaum; Dennis W Dickson; Matthew P Frosch; Bernardino F Ghetti; Kathryn L Lunetta; Li-San Wang; Bradley T Hyman; Walter A Kukull; Tatiana Foroud; Jonathan L Haines; Richard P Mayeux; Margaret A Pericak-Vance; Julie A Schneider; John Q Trojanowski; Lindsay A Farrer; Gerard D Schellenberg; Gary W Beecham; Thomas J Montine; Gyungah R Jun; Alzheimer’s Disease Genetics Consortium

doi:10.1038/s41467-019-14279-8

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

Nat Commun. 2020 Feb 3;11(1):667. doi: 10.1038/s41467-019-14279-8.

Authors

Eric M Reiman^{1

2

3

4}, Joseph F Arboleda-Velasquez⁵, Yakeel T Quiroz⁶, Matthew J Huentelman⁷, Thomas G Beach⁸, Richard J Caselli⁹, Yinghua Chen⁸, Yi Su⁸, Amanda J Myers¹⁰, John Hardy¹¹, Jean Paul Vonsattel¹², Steven G Younkin¹³, David A Bennett¹⁴, Philip L De Jager¹⁵, Eric B Larson¹⁶, Paul K Crane¹⁷, C Dirk Keene¹⁸, M Ilyas Kamboh¹⁹, Julia K Kofler²⁰, Linda Duque²¹, John R Gilbert²², Harry E Gwirtsman²³, Joseph D Buxbaum²⁴, Dennis W Dickson²⁵, Matthew P Frosch²⁶, Bernardino F Ghetti²⁷, Kathryn L Lunetta²⁸, Li-San Wang²⁹, Bradley T Hyman³⁰, Walter A Kukull³¹, Tatiana Foroud³², Jonathan L Haines³³, Richard P Mayeux³⁴, Margaret A Pericak-Vance²², Julie A Schneider¹⁴, John Q Trojanowski²⁹, Lindsay A Farrer^{28

35

36

37}, Gerard D Schellenberg²⁹, Gary W Beecham²², Thomas J Montine³⁸, Gyungah R Jun³⁵; Alzheimer’s Disease Genetics Consortium

Collaborators

Alzheimer’s Disease Genetics Consortium:
Erin Abner, Perrie M Adams, Marilyn S Albert, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S 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 S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Helena C Chui, David H Cribbs, Elizabeth A Crocco, Carlos Cruchaga, Charles DeCarli, Malcolm Dick, Rachelle S Doody, Ranjan Duara, Nilufer Ertekin-Taner, Denis A Evans, Kelley M Faber, Thomas J Fairchild, Kenneth B Fallon, David W Fardo, Martin R Farlow, Steven Ferris, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, Valentina Ghisays, Alison M Goate, Neill 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, Gail P Jarvik, Lee-Way Jin, Anna Karydas, Mindy J Katz, John S K Kauwe, Jeffrey A Kaye, Ronald Kim, Neil W Kowall, Joel H Kramer, Brian W Kunkle, Amanda P Kuzma, Frank M LaFerla, James J Lah, Yuk Ye Leung, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Richard B Lipton, Oscar L Lopez, Constantine G Lyketsos, John Malamon, Daniel C Marson, Eden R Martin, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Stefan McDonough, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Shubhabrata Mukherjee, Adam C Naj, Sid O'Bryant, John M Olichney, Joseph E Parisi, Henry L Paulson, Elaine Peskind, Ronald C Petersen, Aimee Pierce, Wayne W Poon, Huntington Potter, Liming 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, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Juan C Troncoso, Debby W Tsuang, Otto Valladares, 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, Chang-En Yu, Lei Yu, Yi Zhao

Affiliations

¹ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, 901 E Willetta Street, Phoenix, AZ, 85006, USA. [email protected].
² University of Arizona, 714 E Van Buren Street, Phoenix, AZ, 85006, USA. [email protected].
³ Arizona State University, 522 N Central Avenue, Phoenix, AZ, 85004, USA. [email protected].
⁴ Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, 445 N Fifth Street, Phoenix, AZ, 85004, USA. [email protected].
⁵ Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA.
⁶ Departments of Psychiatry and Neurology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁷ Neurogenomics Division, Translational Genomics Research Institute and Arizona Alzheimer's Consortium, 445 N Fifth Street, Phoenix, AZ, 85004, USA.
⁸ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, 901 E Willetta Street, Phoenix, AZ, 85006, USA.
⁹ Mayo Clinic, 13400 E Shea Boulevard, Scottsdale, AZ, 85259, USA.
¹⁰ Department of Psychiatry and Behavioral Science, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA.
¹¹ Department of Molecular Neuroscience, UCL, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
¹² New York Brain Bank and Department of Pathology, New York-Presbyterian Hospital at Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.
¹³ Departments of Neuroscience and Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
¹⁴ Departments of Neurological Sciences and Pathology (Neuropathology), and Rush Alzheimer's Disease Center, Rush University Medical Center, 1725 W Harrison Street, Chicago, IL, 60612, USA.
¹⁵ Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA.
¹⁶ Kaiser Permanente Washington Health Research Institute, 1730 Minor Avenue, Seattle, WA, 98101, USA.
¹⁷ Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98198, USA.
¹⁸ Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98198, USA.
¹⁹ Department of Human Genetics, Alzheimer's Disease Research Center, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
²⁰ Department of Pathology (Neuropathology), University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
²¹ Department of Neurology, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA.
²² John P. Hussman Institute for Human Genomics, Department of Human Genetics, and Dr. John T. Macdonald Foundation, University of Miami, 1501 NW 10th Avenue, Miami, FL, 33136, USA.
²³ Department of Psychiatry, Vanderbilt University, 1601 23rd Avenue South, Nashville, TN, 37212, USA.
²⁴ Departments of Psychiatry, Neuroscience and Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY, 10029, USA.
²⁵ Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
²⁶ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA.
²⁷ Department of Pathology and Laboratory Medicine, Indiana University, 340 West 10th Street, Indianapolis, IN, 46202, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA, 02118, USA.
²⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
³⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
³¹ Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
³² Department of Medical and Molecular Genetics, Indiana University, 410W 10th Street, Indianapolis, IN, 46202, USA.
³³ Institute for Computational Biology and Department of Population and Quantitative Health Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
³⁴ Taub Institute on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center Department of Neurology, Columbia University, 710 West 168th Street, New York, NY, 10032, USA.
³⁵ Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
³⁶ Department of Neurology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
³⁷ Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
³⁸ Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alleles
Alzheimer Disease / genetics*
Alzheimer Disease / metabolism
Apolipoprotein E2 / genetics*
Apolipoprotein E2 / metabolism
Apolipoprotein E3 / genetics
Apolipoprotein E4 / genetics
Brain / metabolism
Female
Genetic Association Studies
Genetic Predisposition to Disease / genetics*
Genotype
Homozygote*
Humans
Male
Middle Aged
Neuropathology
Probability

Substances

Apolipoprotein E2
Apolipoprotein E3
Apolipoprotein E4

Abstract

Publication types

MeSH terms

Substances

Grants and funding