title: Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: the Cache County Dementia Progression Study.
abstract: BACKGROUND
  Single-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1, rs1868402) and the microtubule-associated protein tau (MAPT, rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR-sb). We attempted to validate the latter association in an independent, population-based sample of incident AD cases from the Cache County Dementia Progression Study (DPS).
  
  
  METHODS
  All 92 AD cases from the DPS with a global CDR-sb ≤1 (mild) at initial clinical assessment who were later assessed on CDR-sb data on at least two other time points were genotyped at the two SNPs of interest (rs1868402 and rs3785883). We used linear mixed models to estimate associations between these SNPs and CDR-sb trajectory. All analyses were performed using Proc Mixed in SAS.
  
  
  RESULTS
  Although we observed no association between rs3785883 or rs1868402 alone and change in CDR-sb (P > .10), there was a significant association between a combined genotype model and change in CDR-sb: carriers of the high-risk genotypes at both loci progressed >2.9 times faster than noncarriers (P = .015). When data from DPS were combined with previously published data from WU and ADNI, change in CDR-sb was 30% faster for each copy of the high-risk allele at rs3785883 (P = .0082) and carriers of both high-risk genotypes at both loci progressed 6 times faster (P < .0001) than all others combined.
  
  
  CONCLUSIONS
  We replicate a previous report by Cruchaga et al that specific variations in rs3785883 and rs1868402 are associated with accelerated progression of AD. Further characterization of this association will provide a better understanding of how genetic factors influence the rate of progression of AD and could provide novel insights into preventative and therapeutic strategies.
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Munger
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Crowley
authors.affiliation: Department of Mathematics and Statistics, Utah State University, Logan, UT, USA; Center for Epidemiologic Studies, Utah State University, Logan, UT, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Corcoran
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Center for Epidemiologic Studies, Utah State University, Logan, UT, USA; Department of Family Consumer and Human Development, Utah State University, Logan, UT, USA; Department of Psychology, Utah State University, Logan, UT, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Norton
authors.affiliation: Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: Department of Nutrition Dietetics and Food Sciences, Utah State University, Logan, UT, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Munger
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: John C S
authors.initials: JC
authors.lastname: Breitner
authors.affiliation: Departments of Psychiatry and Medicine, Duke University, Durham, NC, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Welsh-Bohmer
authors.affiliation: Department of Psychiatry, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: Lyketsos
authors.affiliation: Center for Epidemiologic Studies, Utah State University, Logan, UT, USA; Department of Psychology, Utah State University, Logan, UT, USA.
authors.forename: Joann
authors.initials: J
authors.lastname: Tschanz
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA. Electronic address: kauwe@byu.edu.
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D019703:Calcineurin / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012720:Severity of Illness Index; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D019703:Calcineurin; C525676:PPP3R1 protein, human
keywords: Alzheimer's disease; Association; Genetics; MAPT; PPP3R1; Rate of progression