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JAMA Neurol. 2015 Feb;72(2):209-16. doi: 10.1001/jamaneurol.2014.2157.

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

Wang LS1, Naj AC2, Graham RR3, Crane PK4, Kunkle BW5, Cruchaga C6, Murcia JD7, Cannon-Albright L8, Baldwin CT9, Zetterberg H10, Blennow K11, Kukull WA12, Faber KM13, Schupf N14, Norton MC15, Tschanz JT16, Munger RG17, Corcoran CD18, Rogaeva E19; Alzheimer's Disease Genetics Consortium, Lin CF1, Dombroski BA1, Cantwell LB1, Partch A1, Valladares O1, Hakonarson H20, St George-Hyslop P21, Green RC22, Goate AM6, Foroud TM13, Carney RM23, Larson EB24, Behrens TW3, Kauwe JS7, Haines JL25, Farrer LA26, Pericak-Vance MA27, Mayeux R28, Schellenberg GD1; 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 LW, Jun G, 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 CE, Yu L.

Author information

1
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
2
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
3
Department of Human Genetics, Genentech Inc, South San Francisco, California.
4
Department of Medicine, University of Washington, Seattle.
5
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
6
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri7Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, Missouri.
7
Department of Biology, Brigham Young University, Provo, Utah.
8
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City10George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
9
Biomedical Genetics, Department of Medicine, Boston University, Boston, Massachusetts.
10
Institute of Neurology, University College London, London, England13Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska Uni.
11
Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
12
Department of Epidemiology, University of Washington, Seattle.
13
Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
14
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York17Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York18Gertrude H. Sergievsky Center, Columbia.
15
Department of Family, Consumer, and Human Development, Utah State University, Logan20Department of Psychology, Utah State University, Logan.
16
Department of Psychology, Utah State University, Logan.
17
Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan.
18
Department of Mathematics and Statistics, Utah State University, Logan.
19
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
20
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
21
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada25Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, England.
22
Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
23
Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida.
24
Department of Medicine, University of Washington, Seattle28Group Health Research Institute, Seattle, Washington.
25
Center for Human Genetics and Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
26
Department of Biology, Brigham Young University, Provo, Utah30Department of Biostatistics, Boston University, Boston, Massachusetts31Department of Ophthalmology, Boston University, Boston, Massachusetts32Department of Neurology, Boston University, Boston.
27
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida34Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
28
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York18Gertrude H. Sergievsky Center, Columbia University, New York, New York35Department of Neurology, Columbia University, New York, New York.

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.

PMID:
25531812
PMCID:
PMC4324097
DOI:
10.1001/jamaneurol.2014.2157
[Indexed for MEDLINE]
Free PMC Article

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