Dataset Information

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

SUBMITTER: Wang LS

PROVIDER: S-EPMC4324097 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Wang Li-San LS Naj Adam C AC Graham Robert R RR Crane Paul K PK Kunkle Brian W BW Cruchaga Carlos C Murcia Josue D Gonzalez JD Cannon-Albright Lisa L Baldwin Clinton T CT Zetterberg Henrik H Blennow Kaj K Kukull Walter A WA Faber Kelley M KM Schupf Nicole N Norton Maria C MC Tschanz JoAnn T JT Munger Ronald G RG Corcoran Christopher D CD Rogaeva Ekaterina E Lin Chiao-Feng CF Dombroski Beth A BA Cantwell Laura B LB Partch Amanda A Valladares Otto O Hakonarson Hakon H St George-Hyslop Peter P Green Robert C RC Goate Alison M AM Foroud Tatiana M TM Carney Regina M RM Larson Eric B EB Behrens Timothy W TW Kauwe John S K JS Haines Jonathan L JL Farrer Lindsay A LA Pericak-Vance Margaret A MA Mayeux Richard R Schellenberg Gerard D GD Albert Marilyn S MS Albin Roger L RL Apostolova Liana G LG Arnold Steven E SE Barber Robert R Barmada Michael M Barnes Lisa L LL Beach Thomas G TG Becker James T JT Beecham Gary W GW Beekly Duane D Bennett David A DA Bigio Eileen H EH Bird Thomas D TD Blacker Deborah D Boeve Bradley F BF Bowen James D JD Boxer Adam A Burke James R JR Buxbaum Joseph D JD Cairns Nigel J NJ Cao Chuanhai C Carlson Chris S CS Carroll Steven L SL Chui Helena C HC Clark David G DG Cribbs David H DH Crocco Elizabeth A EA DeCarli Charles C DeKosky Steven T ST Demirci F Yesim FY Dick Malcolm M Dickson Dennis W DW Duara Ranjan R Ertekin-Taner Nilufer N Fallon Kenneth B KB Farlow Martin R MR Ferris Steven S Frosch Matthew P MP Galasko Douglas R DR Ganguli Mary M Gearing Marla M Geschwind Daniel H DH Ghetti Bernardino B Gilbert John R JR Glass Jonathan D JD Graff-Radford Neill R NR Growdon John H JH Hamilton Ronald L RL Hamilton-Nelson Kara L KL Harrell Lindy E LE Head Elizabeth E Honig Lawrence S LS Hulette Christine M CM Hyman Bradley T BT Jarvik Gail P GP Jicha Gregory A GA Jin Lee-Way LW Jun Gyungah G Jun Gyungah G Kamboh M Ilyas MI Karydas Anna A Kaye Jeffrey A JA Kim Ronald R Koo Edward H EH Kowall Neil W NW Kramer Joel H JH LaFerla Frank M FM Lah James J JJ Leverenz James B JB Levey Allan I AI Li Gei G Lieberman Andrew P AP Lopez Oscar L OL Lunetta Kathryn L KL Lyketsos Constantine G CG Mack Wendy J WJ Marson Daniel C DC Martin Eden R ER Martiniuk Frank F Mash Deborah C DC Masliah Eliezer E McCormick Wayne C WC McCurry Susan M SM McDavid Andrew N AN McKee Ann C AC Mesulam W Marsel WM Miller Bruce L BL Miller Carol A CA Miller Joshua W JW Montine Thomas J TJ Morris John C JC Murrell Jill R JR Olichney John M JM Parisi Joseph E JE Perry William W Peskind Elaine E Petersen Ronald C RC Pierce Aimee A Poon Wayne W WW Potter Huntington H Quinn Joseph F JF Raj Ashok A Raskind Murray M Reiman Eric M EM Reisberg Barry B Reitz Christiane C Ringman John M JM Roberson Erik D ED Rosen Howard J HJ Rosenberg Roger N RN Sano Mary M Saykin Andrew J AJ Schneider Julie A JA Schneider Lon S LS Seeley William W WW Smith Amanda G AG Sonnen Joshua A JA Spina Salvatore S Stern Robert A RA Tanzi Rudolph E RE Thornton-Wells Tricia A TA Trojanowski John Q JQ Troncoso Juan C JC Tsuang Debby W DW Van Deerlin Vivianna M VM Van Eldik Linda J LJ Vardarajan Badri N BN Vinters Harry V HV Vonsattel Jean Paul JP Weintraub Sandra S Welsh-Bohmer Kathleen A KA Williamson Jennifer J Wishnek Sarah S Woltjer Randall L RL Wright Clinton B CB Younkin Steven G SG Yu Chang-En CE Yu Lei L

JAMA neurology 20150201 2

<h4>Importance</h4>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.<h4>Objective</h4>T ...[more]

PMID: 25531812

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Project description:Pathogenic mutations in the amyloid precursor protein (APP) gene have been described as causing early onset familial Alzheimer disease (AD). We recently identified a rare APP variant encoding an alanine-to-threonine substitution at residue 673 (A673T) that confers protection against development of AD (Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., Hoyte, K., Gustafson, A., Liu, Y., Lu, Y., Bhangale, T., Graham, R. R., Huttenlocher, J., Bjornsdottir, G., Andreassen, O. A., Jönsson, E. G., Palotie, A., Behrens, T. W., Magnusson, O. T., Kong, A., Thorsteinsdottir, U., Watts, R. J., and Stefansson, K. (2012) Nature 488, 96-99). The Ala-673 residue lies within the ?-secretase recognition sequence and is part of the amyloid-? (A?) peptide cleavage product (position 2 of A?). We previously demonstrated that the A673T substitution makes APP a less favorable substrate for cleavage by BACE1. In follow-up studies, we confirm that A673T APP shows reduced cleavage by BACE1 in transfected mouse primary neurons and in isogenic human induced pluripotent stem cell-derived neurons. Using a biochemical approach, we show that the A673T substitution modulates the catalytic turnover rate (V(max)) of APP by the BACE1 enzyme, without affecting the affinity (K(m)) of the APP substrate for BACE1. We also show a reduced level of A?(1-42) aggregation with A2T A? peptides, an observation not conserved in A?(1-40) peptides. When combined in a ratio of 1:9 A?(1-42)/A?(1-40) to mimic physiologically relevant mixtures, A2T retains a trend toward slowed aggregation kinetics. Microglial uptake of the mutant A?(1-42) peptides correlated with their aggregation level. Cytotoxicity of the mutant A? peptides was not dramatically altered. Taken together, our findings demonstrate that A673T, a protective allele of APP, reproducibly reduces amyloidogenic processing of APP and also mildly decreases A? aggregation. These effects could together have an additive or even synergistic impact on the risk of developing AD.

Project description:ImportanceWhile amyloid and neurodegeneration are viewed together as Alzheimer disease pathophysiology (ADP), the factors that influence amyloid and AD-pattern neurodegeneration may be considerably different. Protection from these ADP factors may be important for aging without significant ADP.ObjectiveTo identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration in a population-based sample and to test the hypothesis that "exceptional agers" with advanced ages do not have significant ADP because they have protective factors for amyloid and neurodegeneration.Design, setting, and participantsThis cohort study conducted a prospective analysis of 942 elderly individuals (70-?90 years) with magnetic resonance imaging and Pittsburgh compound B-positron emission tomography scans enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We operationalized "exceptional aging" without ADP by considering individuals 85 years or older to be without significant evidence of ADP.Main outcomes and measuresWe evaluated predictors including demographics, APOE, intellectual enrichment, midlife risk factors (physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia), and the total number of late-life cardiac and metabolic conditions. We used multivariate linear regression models to identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration. Using a subsample of the cohort 85 years of age or older, we computed Cohen d-based effect size estimations to compare the quantitative strength of each predictor variable in their contribution with exceptional aging without ADP.ResultsThe study participants included 423 (45%) women and the average age of participants was 79.7 (5.9) years. Apart from demographics and the APOE genotype, only midlife dyslipidemia was associated with amyloid deposition. Obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. In the 85 years or older cohort, the Cohen d results showed small to moderate effects (effect sizes?>?0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without ADP.Conclusions and relevanceThe protective factors that influence amyloid and AD-pattern neurodegeneration are different. "Exceptional aging" without ADP may be possible with a greater number of protective factors across the lifespan but warrants further investigation.

Dataset Information

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

Publications

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

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