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

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; Vonsattel, Jean Paul; Younkin, Steven G.; Bennett, David A.; 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.

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. 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 and Gyungah R. Jun
Additional contact information
Eric M. Reiman: Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium
Joseph F. Arboleda-Velasquez: Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School
Yakeel T. Quiroz: Massachusetts General Hospital and Harvard Medical School
Matthew J. Huentelman: Translational Genomics Research Institute and Arizona Alzheimer’s Consortium
Thomas G. Beach: Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium
Richard J. Caselli: Mayo Clinic
Yinghua Chen: Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium
Yi Su: Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium
Amanda J. Myers: University of Miami Miller School of Medicine
John Hardy: Institute of Neurology
Jean Paul Vonsattel: New York-Presbyterian Hospital at Columbia University Medical Center
Steven G. Younkin: Mayo Clinic
David A. Bennett: Rush University Medical Center
Philip L. Jager: Columbia University Medical Center
Eric B. Larson: Kaiser Permanente Washington Health Research Institute
Paul K. Crane: University of Washington
C. Dirk Keene: University of Washington
M. Ilyas Kamboh: University of Pittsburgh
Julia K. Kofler: University of Pittsburgh
Linda Duque: University of Miami
John R. Gilbert: University of Miami
Harry E. Gwirtsman: Vanderbilt University
Joseph D. Buxbaum: Mount Sinai School of Medicine
Dennis W. Dickson: Mayo Clinic
Matthew P. Frosch: Massachusetts General Hospital
Bernardino F. Ghetti: Indiana University
Kathryn L. Lunetta: Boston University School of Public Health
Li-San Wang: University of Pennsylvania Perelman School of Medicine
Bradley T. Hyman: Massachusetts General Hospital and Harvard Medical School
Walter A. Kukull: University of Washington
Tatiana Foroud: Indiana University
Jonathan L. Haines: Case Western Reserve University
Richard P. Mayeux: Columbia University
Margaret A. Pericak-Vance: University of Miami
Julie A. Schneider: Rush University Medical Center
John Q. Trojanowski: University of Pennsylvania Perelman School of Medicine
Lindsay A. Farrer: Boston University School of Public Health
Gerard D. Schellenberg: University of Pennsylvania Perelman School of Medicine
Gary W. Beecham: University of Miami
Thomas J. Montine: Stanford University
Gyungah R. Jun: Boston University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14279-8

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