Effect of Genetic Polymorphisms (SNPs) in CHRNA7 Gene on Response to Acetylcholinesterase Inhibitors (AChEI) in Patients with Alzheimer's Disease

Curr Drug Targets. 2017;18(10):1179-1190. doi: 10.2174/1389450116666151001111826.

Abstract

Background: Cholinergic transmission loss is one of the major features in Alzheimer's Disease (AD). Acetylcholinesterase inhibitors (AChEI) are moderately active in AD. α7nAChR (alpha-7 nicotinic acetylcholine receptor), encoded by CHRNA7 (Nicotinic Cholinergic Receptor Alpha-7 gene), is involved in the cholinergic neurotransmission and AD pathogenesis. α7nAChR is a putative receptor of amyloid beta (Aβ). The complex α7nAChR-Aβ is found in neuritic plaques and AD cortical neurons. In normal physiologic conditions, α7nAChR-Aβ interaction leads to receptor activation. Genetic polymorphisms (SNPs) of CHRNA7 and/or CHRFAM7A (fusion gene containing CHRNA7 partial duplication) may be a possible susceptibility trait to dementia, potentially useful to identify high risk or responder individuals. CHRFAM7A-2-bp deletion or CHRNA7 SNPs (rs1514246, rs2337506, rs8027814) seem protective factors in different forms of dementia including AD.

Objective: Correlation between(SNPs) of CHRNA7 and/or CHRFAM7A and cholinesterase inhibitors in AD.

Methods: Literature review.

Results: Among the leading AD therapeutics, Donepezil (DP) and galantamine (AChEI) induce upregulation of α7nAChR protein levels, protecting neurons from degeneration. Patients carrying rs8024987 (C/G) or rs6494223 (C/T) respond better to AChEI. In the caucasic population rs6494223 TT subjects are 7-15% of the total. α7nAChR upregulation induced by DP is higher in lymphocytes from TT subjects than in CC or CT as well as calcium uptake.

Conclusion: The correlation between genetic and functionality data may have an impact on several aspects of disease presentation and therapy, helping in prediction pattern of AD presentation and treatment efficacy. As a consequence it may lead to better patients quality of life and longer periods of self- sufficiency. Moreover, it may contribute to clarify AChEI mechanisms of action.

Keywords: AChEI-cognitive response; AD pathogenesis; Acetylcholinesterase inhibitors (AChEI); CHRNA7; cholinergic transmission; donepezil; galantamine; genetic polymorphisms (SNPs).

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use*
  • Donepezil
  • Female
  • Galantamine / pharmacology
  • Galantamine / therapeutic use
  • Gene Expression Regulation / drug effects
  • Humans
  • Indans / pharmacology
  • Indans / therapeutic use
  • Male
  • Pharmacogenomic Variants
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Polymorphism, Single Nucleotide*
  • Treatment Outcome
  • Up-Regulation
  • alpha7 Nicotinic Acetylcholine Receptor / genetics*

Substances

  • Cholinesterase Inhibitors
  • Chrna7 protein, human
  • Indans
  • Piperidines
  • alpha7 Nicotinic Acetylcholine Receptor
  • Galantamine
  • Donepezil