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

• Published in: Nature communications Vol. 11; no. 1; p. 667
• Main 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.02.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Aged; Aged, 80 and over; Alleles; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Apolipoprotein E; Apolipoprotein E2 - genetics; Apolipoprotein E2 - metabolism; Apolipoprotein E3 - genetics; Apolipoprotein E4; Apolipoprotein E4 - genetics; Brain - metabolism; Dementia; Dementia disorders; Disease control; Female; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Genotype; Genotypes; Health risk assessment; Homozygote; Homozygotes; Humans; Male; Medical treatment; Middle Aged; Neurodegenerative diseases; Neuropathology; Probability; Risk analysis; Risk factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14279-8

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.