We’re moving! Datasets in the NIAGADS database are being transitioned to the DSS database, click to learn more.

Rarity of the Alzheimer disease-protective APP A673T variant in the United States.

TitleRarity of the Alzheimer disease-protective APP A673T variant in the United States.
Publication TypeJournal Article
Year of Publication2015
AuthorsSan Wang, L-, Naj, AC, Graham, RR, Crane, PK, Kunkle, BW, Cruchaga, C, Murcia, JDGonzalez, Cannon-Albright, L, Baldwin, CT, Zetterberg, H, Blennow, K, Kukull, WA, Faber, KM, Schupf, N, Norton, MC, Tschanz, JAT, Munger, RG, Corcoran, CD, Rogaeva, E, Lin, C-F, Dombroski, BA, Cantwell, LB, Partch, A, Valladares, O, Hakonarson, H, St George-Hyslop, P, Green, RC, Goate, AM, Foroud, TM, Carney, RM, Larson, EB, Behrens, TW, Kauwe, JSK, Haines, JL, Farrer, LA, Pericak-Vance, MA, Mayeux, R, Schellenberg, GD, Albert, MS, Albin, RL, Apostolova, LG, Arnold, SE, Barber, R, Barmada, M, Barnes, LL, Beach, TG, Becker, JT, Beecham, GW, Beekly, D, Bennett, DA, Bigio, EH, Bird, TD, Blacker, D, Boeve, BF, Bowen, JD, Boxer, A, Burke, JR, Buxbaum, JD, Cairns, NJ, Cao, C, Carlson, CS, Carroll, SL, Chui, HC, Clark, DG, Cribbs, DH, Crocco, EA, DeCarli, C, DeKosky, ST, F Demirci, Y, Dick, M, Dickson, DW, Duara, R, Ertekin-Taner, N, Fallon, KB, Farlow, MR, Ferris, S, Frosch, MP, Galasko, DR, Ganguli, M, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, JR, Glass, JD, Graff-Radford, NR, Growdon, JH, Hamilton, RL, Hamilton-Nelson, KL, Harrell, LE, Head, E, Honig, LS, Hulette, CM, Hyman, BT, Jarvik, GP, Jicha, GA, Jin, L-W, Jun, G, Jun, G, M Kamboh, I, Karydas, A, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Kramer, JH, LaFerla, FM, Lah, JJ, Leverenz, JB, Levey, AI, Li, G, Lieberman, AP, Lopez, OL, Lunetta, KL, Lyketsos, CG, Mack, WJ, Marson, DC, Martin, ER, Martiniuk, F, Mash, DC, Masliah, E, McCormick, WC, McCurry, SM, McDavid, AN, McKee, AC, W Mesulam, M, Miller, BL, Miller, CA, Miller, JW, Montine, TJ, Morris, JC, Murrell, JR, Olichney, JM, Parisi, JE, Perry, W, Peskind, E, Petersen, RC, Pierce, A, Poon, WW, Potter, H, Quinn, JF, Raj, A, Raskind, M, Reiman, EM, Reisberg, B, Reitz, C, Ringman, JM, Roberson, ED, Rosen, HJ, Rosenberg, RN, Sano, M, Saykin, AJ, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Tanzi, RE, Thornton-Wells, TA, Trojanowski, JQ, Troncoso, JC, Tsuang, DW, Van Deerlin, VM, Van Eldik, LJ, Vardarajan, BN, Vinters, HV, Vonsattel, JPaul, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Wishnek, S, Woltjer, RL, Wright, CB, Younkin, SG, Yu, C-E, Yu, L
Corporate AuthorsAlzheimer's Disease Genetics Consortium, National Institute on Aging-Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study
JournalJAMA Neurol
Volume72
Issue2
Pagination209-16
Date Published2015 Feb
ISSN2168-6157
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Case-Control Studies, Female, Genotype, Humans, Male, Pedigree, Protective Factors, Sweden, United States
Abstract

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.

DOI10.1001/jamaneurol.2014.2157
Alternate JournalJAMA Neurol
PubMed ID25531812
PubMed Central IDPMC4324097
Grant ListP30 AG013854 / AG / NIA NIH HHS / United States
R01 AG11380 / AG / NIA NIH HHS / United States
R01 HL108623 / HL / NHLBI NIH HHS / United States
UL1 TR001445 / TR / NCATS NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
M01 RR000096 / RR / NCRR NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
MO1 RR00096 / RR / NCRR NIH HHS / United States
R01 AG009029 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG016577 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG042611 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
R01 HG02213 / HG / NHGRI NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
P50 AG016575 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01MH080295 / MH / NIMH NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
R01AG3272 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
P30 AG08051 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
089703 / / Wellcome Trust / United Kingdom
AG002219 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
R01 AG007584 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
U01 AG16976 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
U24 AG026390 / AG / NIA NIH HHS / United States
K24 AG027841 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
UL1 RR025777 / RR / NCRR NIH HHS / United States
R01 CA129769 / CA / NCI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
U01 AG010483 / AG / NIA NIH HHS / United States
K02NS 059729 / NS / NINDS NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U01 AG06781 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
P01 AG010491 / AG / NIA NIH HHS / United States
R01 HG002213 / HG / NHGRI NIH HHS / United States
R01 AG021547 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
R01 AG019757 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
R01 AG30146 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
R01 AG021136 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
UL1 TR001417 / TR / NCATS NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
K02 NS059729 / NS / NINDS NIH HHS / United States
UL1 RR02777 / RR / NCRR NIH HHS / United States
P50 AG016576 / AG / NIA NIH HHS / United States
R01 AG031272 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
R01 HL 108623 / HL / NHLBI NIH HHS / United States
081864 / / Wellcome Trust / United Kingdom
U24AG026390 / AG / NIA NIH HHS / United States
/ / Wellcome Trust / United Kingdom
AG021547 / AG / NIA NIH HHS / United States
R01 AG011380 / AG / NIA NIH HHS / United States
AG005138 / AG / NIA NIH HHS / United States
R01 AG21136 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States