title: Rarity of the Alzheimer disease-protective APP A673T variant in the United States.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Naj
authors.affiliation: Department of Human Genetics, Genentech Inc, South San Francisco, California.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Department of Medicine, University of Washington, Seattle.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Kunkle
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah.
authors.forename: Josue D Gonzalez
authors.initials: JD
authors.lastname: Murcia
authors.affiliation: 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.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cannon-Albright
authors.affiliation: Biomedical Genetics, Department of Medicine, Boston University, Boston, Massachusetts.
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.affiliation: 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.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Epidemiology, University of Washington, Seattle.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Faber
authors.affiliation: 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.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupf
authors.affiliation: Department of Family, Consumer, and Human Development, Utah State University, Logan20Department of Psychology, Utah State University, Logan.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Norton
authors.affiliation: Department of Psychology, Utah State University, Logan.
authors.forename: JoAnn T
authors.initials: JT
authors.lastname: Tschanz
authors.affiliation: Department of Nutrition, Dietetics, and Food Sciences, Utah State University, Logan.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Munger
authors.affiliation: Department of Mathematics and Statistics, Utah State University, Logan.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Corcoran
authors.affiliation: Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Chiao-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Dombroski
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Cantwell
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Partch
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Otto
authors.initials: O
authors.lastname: Valladares
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.affiliation: Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: 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.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Carney
authors.affiliation: Department of Medicine, University of Washington, Seattle28Group Health Research Institute, Seattle, Washington.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Department of Human Genetics, Genentech Inc, South San Francisco, California.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.affiliation: Department of Biology, Brigham Young University, Provo, Utah.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Center for Human Genetics and Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: 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.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: 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.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Albert
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Liana G
authors.initials: LG
authors.lastname: Apostolova
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.forename: Robert
authors.initials: R
authors.lastname: Barber
authors.forename: Michael
authors.initials: M
authors.lastname: Barmada
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Barnes
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: James T
authors.initials: JT
authors.lastname: Becker
authors.forename: Gary W
authors.initials: GW
authors.lastname: Beecham
authors.forename: Duane
authors.initials: D
authors.lastname: Beekly
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Deborah
authors.initials: D
authors.lastname: Blacker
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: James D
authors.initials: JD
authors.lastname: Bowen
authors.forename: Adam
authors.initials: A
authors.lastname: Boxer
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Cao
authors.forename: Chris S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Steven L
authors.initials: SL
authors.lastname: Carroll
authors.forename: Helena C
authors.initials: HC
authors.lastname: Chui
authors.forename: David G
authors.initials: DG
authors.lastname: Clark
authors.forename: David H
authors.initials: DH
authors.lastname: Cribbs
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Crocco
authors.forename: Charles
authors.initials: C
authors.lastname: DeCarli
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dick
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Ranjan
authors.initials: R
authors.lastname: Duara
authors.forename: Nilufer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Fallon
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.forename: Steven
authors.initials: S
authors.lastname: Ferris
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.forename: Mary
authors.initials: M
authors.lastname: Ganguli
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: John H
authors.initials: JH
authors.lastname: Growdon
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Kara L
authors.initials: KL
authors.lastname: Hamilton-Nelson
authors.forename: Lindy E
authors.initials: LE
authors.lastname: Harrell
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Honig
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hulette
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Jicha
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.forename: Gyungah
authors.initials: G
authors.lastname: Jun
authors.forename: Gyungah
authors.initials: G
authors.lastname: Jun
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kaye
authors.forename: Ronald
authors.initials: R
authors.lastname: Kim
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
authors.forename: Neil W
authors.initials: NW
authors.lastname: Kowall
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.forename: Gei
authors.initials: G
authors.lastname: Li
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Constantine G
authors.initials: CG
authors.lastname: Lyketsos
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Mack
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Marson
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Frank
authors.initials: F
authors.lastname: Martiniuk
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Wayne C
authors.initials: WC
authors.lastname: McCormick
authors.forename: Susan M
authors.initials: SM
authors.lastname: McCurry
authors.forename: Andrew N
authors.initials: AN
authors.lastname: McDavid
authors.forename: Ann C
authors.initials: AC
authors.lastname: McKee
authors.forename: W Marsel
authors.initials: WM
authors.lastname: Mesulam
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Carol A
authors.initials: CA
authors.lastname: Miller
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Miller
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Jill R
authors.initials: JR
authors.lastname: Murrell
authors.forename: John M
authors.initials: JM
authors.lastname: Olichney
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: William
authors.initials: W
authors.lastname: Perry
authors.forename: Elaine
authors.initials: E
authors.lastname: Peskind
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Aimee
authors.initials: A
authors.lastname: Pierce
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.forename: Ashok
authors.initials: A
authors.lastname: Raj
authors.forename: Murray
authors.initials: M
authors.lastname: Raskind
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Barry
authors.initials: B
authors.lastname: Reisberg
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.forename: Roger N
authors.initials: RN
authors.lastname: Rosenberg
authors.forename: Mary
authors.initials: M
authors.lastname: Sano
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Smith
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Sonnen
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spina
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stern
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Tricia A
authors.initials: TA
authors.lastname: Thornton-Wells
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.forename: Badri N
authors.initials: BN
authors.lastname: Vardarajan
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Welsh-Bohmer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williamson
authors.forename: Sarah
authors.initials: S
authors.lastname: Wishnek
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Clinton B
authors.initials: CB
authors.lastname: Wright
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Chang-En
authors.initials: CE
authors.lastname: Yu
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010375:Pedigree; D065840:Protective Factors; D013548:Sweden / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor