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Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: The Cache County Dementia Progression Study
Author(s) -
Peterson David,
Munger Caitlin,
Crowley Jared,
Corcoran Chris,
Cruchaga Carlos,
Goate Alison M.,
Norton Maria C.,
Green Robert C.,
Munger Ronald G.,
Breitner John C.S.,
WelshBohmer Kathleen A.,
Lyketsos Constantine,
Tschanz JoAnn,
Kauwe John S.K.
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.02.010
Subject(s) - clinical dementia rating , dementia , single nucleotide polymorphism , alzheimer's disease , genotype , oncology , population , tau protein , alzheimer's disease neuroimaging initiative , medicine , disease , genetics , biology , gene , environmental health
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.