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

National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study, Alzheimer's Disease Genetics Consortium

Research output: Contribution to journalArticle

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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 samplingmethods. 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 variantwere 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.

Original languageEnglish (US)
Pages (from-to)209-216
Number of pages8
JournalJAMA Neurology
Volume72
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Amyloid beta-Protein Precursor
Alzheimer Disease
Genes
Sweden
Alanine
Alleles
Genotype
Population
Iceland
Alzheimer's Disease
Precursor
Protein
Gene
Threonine
Nuclear Family
Age of Onset
Case-Control Studies
Cohort Studies
Mothers
Prospective Studies

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study, & Alzheimer's Disease Genetics Consortium (2015). Rarity of the alzheimer disease-protective APP A673T variant in the United States. JAMA Neurology, 72(2), 209-216. https://doi.org/10.1001/jamaneurol.2014.2157

Rarity of the alzheimer disease-protective APP A673T variant in the United States. / National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study; Alzheimer's Disease Genetics Consortium.

In: JAMA Neurology, Vol. 72, No. 2, 01.02.2015, p. 209-216.

Research output: Contribution to journalArticle

National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study & Alzheimer's Disease Genetics Consortium 2015, 'Rarity of the alzheimer disease-protective APP A673T variant in the United States', JAMA Neurology, vol. 72, no. 2, pp. 209-216. https://doi.org/10.1001/jamaneurol.2014.2157
National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study, Alzheimer's Disease Genetics Consortium. Rarity of the alzheimer disease-protective APP A673T variant in the United States. JAMA Neurology. 2015 Feb 1;72(2):209-216. https://doi.org/10.1001/jamaneurol.2014.2157
National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study ; Alzheimer's Disease Genetics Consortium. / Rarity of the alzheimer disease-protective APP A673T variant in the United States. In: JAMA Neurology. 2015 ; Vol. 72, No. 2. pp. 209-216.
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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 samplingmethods. 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 variantwere 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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T1 - Rarity of the alzheimer disease-protective APP A673T variant in the United States

AU - National Institute on Aging-Late-Onset Alzheimer's Disease (NIA-LOAD) Family Study

AU - Alzheimer's Disease Genetics Consortium

AU - Wang, Li San

AU - Naj, Adam C.

AU - Graham, Robert R.

AU - Crane, Paul K.

AU - Kunkle, Brian W.

AU - Cruchaga, Carlos

AU - Gonzalez Murcia, Josue D.

AU - Cannon-Albright, Lisa

AU - Baldwin, Clinton T.

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Kukull, Walter A.

AU - Faber, Kelley M.

AU - Schupf, Nicole

AU - Norton, Maria C.

AU - Tschanz, JoAnn T.

AU - Munger, Ronald G.

AU - Corcoran, Christopher D.

AU - Rogaeva, Ekaterina

AU - Albert, Marilyn S.

AU - Albin, Roger L.

AU - Apostolova, Liana G.

AU - Arnold, Steven E.

AU - Barber, Robert

AU - Barmada, M. Michael

AU - Barnes, Lisa L.

AU - Beach, Thomas G.

AU - Becker, James T.

AU - Beecham, Gary W.

AU - Beekly, Duane

AU - Bennett, David A.

AU - Bigio, Eileen H.

AU - Bird, Thomas D.

AU - Blacker, Deborah

AU - Boeve, Bradley F.

AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Buxbaum, Joseph D.

AU - Cairns, Nigel J.

AU - Cao, Chuanhai

AU - Carlson, Chris S.

AU - Carroll, Steven L.

AU - Chui, Helena C.

AU - Clark, David G.

AU - Cribbs, David H.

AU - Crocco, Elizabeth A.

AU - DeCarli, Charles

AU - DeKosky, Steven T.

AU - Rosenberg, Roger N.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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 samplingmethods. 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 variantwere 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.

AB - 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 samplingmethods. 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 variantwere 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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