Variants in <i>PPP3R1</i> and <i>MAPT</i> are associated with more rapid functional decline in Alzheimer's disease: The Cache County Dementia Progression Study

Alzheimer's & Dementia - Tập 10 - Trang 366-371 - 2014
David Peterson1, Caitlin Munger1, Jared Crowley1, Chris Corcoran2,3, Carlos Cruchaga4, Alison M. Goate5,6, Maria C. Norton3,7,8, Robert C. Green9, Ronald G. Munger10, John C.S. Breitner11, Kathleen A. Welsh-Bohmer12, Constantine Lyketsos13, JoAnn Tschanz3,8, John S.K. Kauwe1
1Department of Biology, Brigham Young University, Provo, UT, USA
2Department of Mathematics and Statistics, Utah State University, Logan, UT, USA
3Center for Epidemiologic Studies Utah State University Logan UT USA
4Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
5Department of Psychiatry, Washington University School of Medicine, St. Louis, Mo., USA
6Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
7Department of Family Consumer and Human Development Utah State University Logan UT USA
8Department of Psychology, Utah State University, Logan, UT, USA
9Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
10Department of Nutrition Dietetics and Food Sciences, Utah State University, Logan, UT, USA
11Department of Psychiatry, McGill University, Montreal, Quebec, Canada
12Departments of Psychiatry and Medicine, Duke University, Durham, NC, USA
13Department of Psychiatry, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA

Tóm tắt

AbstractBackgroundSingle‐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).MethodsAll 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.ResultsAlthough 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.ConclusionsWe 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.

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Alzheimer's & Dementia

Tập 10

366-371

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