A Polymorphism Cluster at the 2q12 locus May Predict Response to Piromelatine in Patients with Mild Alzheimer’s Disease

L. S. Schneider*, M. Laudon, T. Nir, J. Caceres, G. Ianniciello, M. Capulli, N. Zisapel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Piromelatine is a novel melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptors agonist developed for mild Alzheimer’s disease (AD). In a randomized, placebo-controlled, dose-ranging study (ReCognition) of piromelatine (5, 20, and 50 mg daily for 6 months) in participants with mild dementia due to AD (n=371, age 60–85 years), no statistically significant differences were found between the piromelatine and placebo-treated groups on the primary (i.e., computerized neuropsychological test battery (cNTB)) and secondary outcomes (ADCS-CGIC, ADCS-MCI-ADL, ADAS-cog14, NPI, and Pittsburgh Sleep Quality Index (PSQI)) nor were there safety concerns (https://clinicaltrials.gov/ct2/show/NCT02615002). Objectives: This study was aimed at identifying genetic markers predicting piromelatine treatment response using a genome-wide association approach (GWAS). Design: Variant genotyping of a combined whole genome and whole exome sequencing was performed using DNA extracted from lymphocytes from consenting participants. The general case-control allelic test was performed on piromelatine-treated participants, taking “responders” (i.e., >0.125 change from baseline in the cNTB) as cases and “non responders” as controls, using a Cochran-Armitage trend test. Setting: 58 outpatient clinics in the US. Participants: 371 participants were randomized in the trial; 107 provided informed consent for genotyping. Results: The GWAS sample did not differ from the full study cohort in demographics, baseline characteristics, or response to piromelatine. Six single-nucleotide polymorphisms (SNPs) in chromosome 2q12 (2:107,510,000-107,540,000) were associated with response (p-value < 1×10 −4 each). Post hoc analyses suggested that the carriers of the 2q12 polymorphism cluster (27% of the GWAS sample) improved significantly on the cNTB on piromelatine as compared to placebo but significantly worsened on the ADAS-Cog14 and PSQI. By contrast, “non-carriers” improved significantly with piromelatine compared to placebo on the ADAS-Cog14 (2.91 (N=23) with piromelatine 20 mg vs 1.65 (N=19) with placebo (p=0.03)) and PSQI. Conclusions: The 2q12 (2:107,510,000-107,540,000) 5–6 SNPs cluster may predict efficacy of piromelatine for mild AD. These findings warrant further investigation in a larger, prospective early-stage AD clinical trial for patients who are non-carriers of the 2q12 polymorphism cluster.

Original languageEnglish
Pages (from-to)247-254
Number of pages8
JournalThe journal of prevention of Alzheimer's disease
Volume9
Issue number2
DOIs
StatePublished - Apr 2022

Keywords

  • ADAS-cog
  • Alzheimer’s disease
  • GWAS
  • Piromelatine
  • SNP
  • clinical trials
  • cognition
  • sleep

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