Exploratory analysis of seven Alzheimer's disease genes: disease progression

• Authors: Agustin Ruiz, Memory Clinic of Fundació ACE; Isabel Hernandez, Memory Clinic of Fundació ACE; Maitee Ronsende-Roca, Memory Clinic of Fundació ACE; Antonio Gonzalez-Perez, Neocodex; Emma Rodriguez-Noriega, Memory Clinic of Fundació ACE; Reposo Ramirez-Lorca, Neocodex; Ana Mauleon, Memory Clinic of Fundació ACE; Concha Moreno-Rey, Neocodex; Lucie Boswell, Kings College London; Larry Tune, Emory University; Sergi Valero, Memory Clinic of Fundació ACE; Montserrat Alegret, Memory Clinic of Fundació ACE; Javier Gayan, Neocodex; James T. Becker, University of Pittsburgh; Luis Miguel Real, Neocodex; Lluis Tarraga, Memory Clinic of Fundació ACE; Clive Ballard, Kings College London; Michael Terrin, University of Maryland; Stephanie Sherman, Emory University; Haydeh Payami, New York State Department of Health; Oscar L. Lopez, Universitat Autònoma de Barcelona; Jacobo E. Mintzer, Medical University of South Carolina; Merce Boada, Memory Clinic of Fundació ACE
• Journal Title: Neurobiology of Aging
• Volume: Volume 34, Number 4
• Publisher: Elsevier | 2013-04-01, Pages 1310.e1-1310.e7
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.neurobiolaging.2012.08.014
• Subjects: Biology, Genetics; Biology, Neuroscience; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Geriatrics & Gerontology; Neurosciences; Neurosciences & Neurology; GWAS; Alzheimer's disease; SNP; Disease progression; Mixed models; Genetics; Pharmacogenetics; MILD COGNITIVE IMPAIRMENT; GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-E; IDENTIFIES VARIANTS; COMMON VARIANTS; TYPE-4 ALLELE; ONSET; CONSENSUS; CD2AP; EPHA1

Abstract

The relationships between genome wide association study-identified and replicated genetic variants associated with Alzheimer's disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. Seven hundred and one AD patients with at least 3 different cognitive evaluations and genotypic information for APOE and 6 genome wide association study-significant single-nucleotide polymorphisms were selected for this study. Mean differences in Global Deterioration Score and Mini Mental State Examination (MMSE) were evaluated using nonparametric tests, general linear model and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor, memantine, or both. Relationships between therapeutic protocols, genetic markers, and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared with GG carriers at the end of the follow-up (MMSE mean difference = -0.57; 95% confidence interval, -1.145 to 0.009; p = 0.047). This observation remained unaltered after covariate adjustments although it did not achieve predefined multiple testing significance threshold. The PICALM single-nucleotide polymorphism also displayed a significant effect protecting against rapid progression during pharmacogenetic assays although its observed effect displayed heterogeneity among AD therapeutic protocols (p = 0.039). None of the studied genetic markers were convincingly linked to AD progression or drug response. However, by using different statistical approaches, the PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.