Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
Wang, Li-San PhD 1; Naj, Adam C. PhD 2; Graham, Robert R. PhD 3; Crane, Paul K. MD; MPH 4; Kunkle, Brian W. PhD; MPH 5; Cruchaga, Carlos PhD 6,7; Murcia, Josue D. Gonzalez BS 8; Cannon-Albright, Lisa PhD 9,10; Baldwin, Clinton T. PhD 11; Zetterberg, Henrik MD; PhD 12,13; Blennow, Kaj MD 13; Kukull, Walter A. PhD 14; Faber, Kelley M. MS 15; Schupf, Nicole PhD; DrPH 16,17,18; Norton, Maria C. PhD 19,20; Tschanz, JoAnn T. PhD 20; Munger, Ronald G. MPH; PhD 21; Corcoran, Christopher D. PhD 22; Rogaeva, Ekaterina PhD 23; Alzheimer's Disease Genetics Consortium; Lin, Chiao-Feng PhD 1; Dombroski, Beth A. PhD 1; Cantwell, Laura B. MPH 1; Partch, Amanda MS 1; Valladares, Otto MS 1; Hakonarson, Hakon MD; PhD 24; St George-Hyslop, Peter MD; FRCP 23,25; Green, Robert C. MD; MPH 26; Goate, Alison M. DPhil 6,7; Foroud, Tatiana M. PhD 15; Carney, Regina M. MD 27; Larson, Eric B. MD; MPH 4,28; Behrens, Timothy W. MD 3; Kauwe, John S. K. PhD 8; Haines, Jonathan L. PhD 29; Farrer, Lindsay A. PhD 8,30,31,32,33; Pericak-Vance, Margaret A. PhD 5,34; Mayeux, Richard MD 17,18,35; Schellenberg, Gerard D. PhD 1; Albert, Marilyn S. PhD 36; Albin, Roger L. MD 37,38,39; Apostolova, Liana G. MD 40; Arnold, Steven E. MD 41; Barber, Robert PhD 42; Barmada, M. Michael PhD 43; Barnes, Lisa L. PhD 44,45; Beach, Thomas G. MD; PhD 46; Becker, James T. PhD 47,48,49; Beecham, Gary W. PhD 50,51; Beekly, Duane BS 52; Bennett, David A. MD 44,53; Bigio, Eileen H. MD 54,55; Bird, Thomas D. MD 56,57; Blacker, Deborah MD; ScD 58,59; Boeve, Bradley F. MD 60; Bowen, James D. MD 61; Boxer, Adam MD; PhD 62; Burke, James R. MD; PhD 63; Buxbaum, Joseph D. PhD 64,65,66; Cairns, Nigel J. PhD 67; Cao, Chuanhai PhD 68; Carlson, Chris S. 69; Carroll, Steven L. MD; PhD 70; Chui, Helena C. MD 71; Clark, David G. MD 72; Cribbs, David H. PhD 73; Crocco, Elizabeth A. MD 74; DeCarli, Charles MD 75; DeKosky, Steven T. MD 76,77; Demirci, F. Yesim MD 43; Dick, Malcolm PhD 78; Dickson, Dennis W. MD 79; Duara, Ranjan MD 80; Ertekin-Taner, Nilufer MD; PhD 79,81; Fallon, Kenneth B. MD 70; Farlow, Martin R. MD 82; Ferris, Steven PhD 83; Frosch, Matthew P. MD; PhD 84; Galasko, Douglas R. MD 85; Ganguli, Mary MD; PhD 47; Gearing, Marla PhD 86,87; Geschwind, Daniel H. MD; PhD 88; Ghetti, Bernardino MD 89; Gilbert, John R. PhD 50,51; Glass, Jonathan D. MD 90; Graff-Radford, Neill R. MD 79,81; Growdon, John H. MD 91; Hamilton, Ronald L. MD 92; Hamilton-Nelson, Kara L. 50; Harrell, Lindy E. MD; PhD 72; Head, Elizabeth PhD 93; Honig, Lawrence S. MD; PhD 94,95; Hulette, Christine M. MD 96; Hyman, Bradley T. MD; PhD 91; Jarvik, Gail P. MD; PhD 97,98; Jicha, Gregory A. MD; PhD 99; Jin, Lee-Way MD; PhD 100; Jun, Gyungah PhD 101,102,103; Kamboh, M. Ilyas PhD 43,104; Karydas, Anna BA 62; Kaye, Jeffrey A. MD 105,106; Kim, Ronald MD 107; Koo, Edward H. MD 85; Kowall, Neil W. MD 108,109; Kramer, Joel H. PhD 110; Kramer, Patricia PhD 105,111; LaFerla, Frank M. PhD 112; Lah, James J. MD; PhD 90; Leverenz, James B. MD 113; Levey, Allan I. MD; PhD 90; Li, Ge MD; PhD 114; Lieberman, Andrew P. MD; PhD 115; Lopez, Oscar L. MD 104; Lunetta, Kathryn L. PhD 102; Lyketsos, Constantine G. MD; MHS 116; Mack, Wendy J. PhD 117; Marson, Daniel C. JD; PhD 72; Martin, Eden R. PhD 50,51; Martiniuk, Frank PhD 118; Mash, Deborah C. PhD 119; Masliah, Eliezer MD 85,120; McCormick, Wayne C. 121; McCurry, Susan M. PhD 122; McDavid, Andrew N. BA 69; McKee, Ann C. MD 108,109; Mesulam, M. Marsel MD 55,123; Miller, Bruce L. MD 62; Miller, Carol A. MD 124; Miller, Joshua W. MD 100; Montine, Thomas J. MD; PhD 113; Morris, John C. MD 67,125; Murrell, Jill R. PhD 89,126; Olichney, John M. MD 75; Parisi, Joseph E. MD 127,128; Perry, William 50; Peskind, Elaine MD 114; Petersen, Ronald C. MD; PhD 60; Pierce, Aimee 73; Poon, Wayne W. PhD 78; Potter, Huntington PhD 68; Quinn, Joseph F. MD 105; Raj, Ashok MD 68; Raskind, Murray MD 114; Reiman, Eric M. MD 129,130,131; Reisberg, Barry MD 83,132; Reitz, Christiane MD; PhD 94,95,133; Ringman, John M. MD; MS 40; Roberson, Erik D. MD; PhD 72; Rosen, Howard J. MD 62; Rosenberg, Roger N. MD 134; Sano, Mary PhD 65; Saykin, Andrew J. PsyD 126,135; Schneider, Julie A. MD 44,136; Schneider, Lon S. MD 71,137; Seeley, William W. MD 62; Smith, Amanda G. 68; Sonnen, Joshua A. MD 113; Spina, Salvatore MD 89; Stern, Robert A. PhD 108; Tanzi, Rudolph E. PhD 91; Thornton-Wells, Tricia A. PhD 138; Trojanowski, John Q. MD; PhD 139; Troncoso, Juan C. MD 140; Tsuang, Debby W. MD 56,114; Van Deerlin, Vivianna M. MD; PhD 139; Van Eldik, Linda J. PhD 141; Vardarajan, Badri N. PhD 94,95,133; Vinters, Harry V. MD 40,142; Vonsattel, Jean Paul MD 94,143; Weintraub, Sandra PhD 55,144; Welsh-Bohmer, Kathleen A. PhD 63,145; Williamson, Jennifer MS; MPH 94; Wishnek, Sarah 50; Woltjer, Randall L. MD; PhD 146; Wright, Clinton B. MD; MS 147; Younkin, Steven G. MD; PhD 79; Yu, Chang-En PhD 121; Yu, Lei PhD 44
[Article]
JAMA Neurology.
72(2):209-216, February 2015.
(Format: HTML, PDF)
Importance: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
Objective: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden.
Design, Setting, and Participants: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources.
Main Outcomes and Measures: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies).
Results: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673.
Conclusions and Relevance: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
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