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 et al.
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
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P50 AG023501 / AG / NIA NIH HHS / United States
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089703 / / Wellcome Trust / United Kingdom
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/ / Wellcome Trust / United Kingdom
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