title: Exploratory analysis of seven Alzheimer's disease genes: disease progression.
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.
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain. aruiz@fundacioace.com
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández
authors.forename: Maiteé
authors.initials: M
authors.lastname: Ronsende-Roca
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Pérez
authors.forename: Emma
authors.initials: E
authors.lastname: Rodriguez-Noriega
authors.forename: Reposo
authors.initials: R
authors.lastname: Ramírez-Lorca
authors.forename: Ana
authors.initials: A
authors.lastname: Mauleón
authors.forename: Concha
authors.initials: C
authors.lastname: Moreno-Rey
authors.forename: Lucie
authors.initials: L
authors.lastname: Boswell
authors.forename: Larry
authors.initials: L
authors.lastname: Tune
authors.forename: Sergi
authors.initials: S
authors.lastname: Valero
authors.forename: Montserrat
authors.initials: M
authors.lastname: Alegret
authors.forename: Javier
authors.initials: J
authors.lastname: Gayán
authors.forename: James T
authors.initials: JT
authors.lastname: Becker
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Real
authors.forename: Lluís
authors.initials: L
authors.lastname: Tárraga
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.forename: Michael
authors.initials: M
authors.lastname: Terrin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sherman
authors.forename: Haydeh
authors.initials: H
authors.lastname: Payami
authors.forename: Oscar L
authors.initials: OL
authors.lastname: López
authors.forename: Jacobo E
authors.initials: JE
authors.lastname: Mintzer
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology
chemical_list: D005819:Genetic Markers