Pharmacogenomics in Alzheimer's disease: A genome-wide association study of response to cholinesterase inhibitors

Filippo Martinelli-Boneschi, Giacomo Giacalone, Giuseppe Magnani, Gloria Biella, Elisabetta Coppi, Roberto Santangelo, Paola Brambilla, Federica Esposito, Sara Lupoli, Francesca Clerici, Luisa Benussi, Roberta Ghidoni, Daniela Galimberti, Rosanna Squitti, Annamaria Confaloni, Giuseppe Bruno, Sabrina Pichler, Manuel Mayhaus, Matthias Riemenschneider, Claudio MarianiGiancarlo Comi, Elio Scarpini, Giuliano Binetti, Gianluigi Forloni, Massimo Franceschi, Diego Albani

Research output: Contribution to journalArticlepeer-review


We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer's disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ≤1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (pcombined = 2.9 × 10-5, beta regression coefficient: 1.61) and rs17798800A (pcombined = 6.8 × 10-6, odds ratio = 0.38, 95% confidence interval = 0.25-0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase-anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field.

Original languageEnglish
JournalNeurobiology of Aging
Issue number6
Publication statusPublished - Jun 2013


  • Acetylcholinesterase inhibitors
  • Alzheimer's disease
  • Genetics
  • Genome-wide association study
  • Pharmacogenomics

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology


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