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

Publication ,  Journal Article
Wang, L-S; Naj, AC; Graham, RR; Crane, PK; Kunkle, BW; Cruchaga, C; Murcia, JDG; Cannon-Albright, L; Baldwin, CT; Zetterberg, H; Blennow, K ...
Published in: JAMA Neurol
February 2015

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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Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

February 2015

Volume

72

Issue

2

Start / End Page

209 / 216

Location

United States

Related Subject Headings

  • United States
  • Sweden
  • Protective Factors
  • Pedigree
  • Male
  • Humans
  • Genotype
  • Female
  • Case-Control Studies
  • Amyloid beta-Protein Precursor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, L.-S., Naj, A. C., Graham, R. R., Crane, P. K., Kunkle, B. W., Cruchaga, C., … Yu, L. (2015). Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol, 72(2), 209–216. https://doi.org/10.1001/jamaneurol.2014.2157
Wang, Li-San, Adam C. Naj, Robert R. Graham, Paul K. Crane, Brian W. Kunkle, Carlos Cruchaga, Josue D Gonzalez Murcia, et al. “Rarity of the Alzheimer disease-protective APP A673T variant in the United States.JAMA Neurol 72, no. 2 (February 2015): 209–16. https://doi.org/10.1001/jamaneurol.2014.2157.
Wang L-S, Naj AC, Graham RR, Crane PK, Kunkle BW, Cruchaga C, et al. Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 2015 Feb;72(2):209–16.
Wang, Li-San, et al. “Rarity of the Alzheimer disease-protective APP A673T variant in the United States.JAMA Neurol, vol. 72, no. 2, Feb. 2015, pp. 209–16. Pubmed, doi:10.1001/jamaneurol.2014.2157.
Wang L-S, Naj AC, Graham RR, Crane PK, Kunkle BW, Cruchaga C, Murcia JDG, Cannon-Albright L, Baldwin CT, Zetterberg H, Blennow K, Kukull WA, Faber KM, Schupf N, Norton MC, Tschanz JT, Munger RG, Corcoran CD, Rogaeva E, Alzheimer’s Disease Genetics Consortium, 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, National Institute on Aging-Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study, 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, Demirci FY, 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, Kamboh MI, 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, Mesulam WM, 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 JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu C-E, Yu L. Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 2015 Feb;72(2):209–216.

Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

February 2015

Volume

72

Issue

2

Start / End Page

209 / 216

Location

United States

Related Subject Headings

  • United States
  • Sweden
  • Protective Factors
  • Pedigree
  • Male
  • Humans
  • Genotype
  • Female
  • Case-Control Studies
  • Amyloid beta-Protein Precursor