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. 2013 Dec 31;8(12):e84059.
doi: 10.1371/journal.pone.0084059. eCollection 2013.

CHRNA7 polymorphisms and response to cholinesterase inhibitors in Alzheimer's disease

Pei-Hsuan Weng  1 , Jen-Hau Chen  2 , Ta-Fu Chen  3 , Yu Sun  4 , Li-Li Wen  5 , Ping-Keung Yip  6 , Yi-Min Chu  7 , Yen-Ching Chen  8
Affiliations

CHRNA7 polymorphisms and response to cholinesterase inhibitors in Alzheimer's disease

Pei-Hsuan Weng et al. PLoS One. .

Abstract

Background: CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response.

Methods: Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≥ 2 between baseline and 6 months after ChEI treatment.

Results: AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47-8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38-8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine.

Conclusion: For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. CHRNA7 linkage disequilibrium (LD) plot.
The plot was generated by applying the Haploview program to genotype data from this study. The level of pairwise D', which indicates the degree of LD between two SNPs, is shown in the LD structure in gray scale. The level of pairwise r2, which indicates the degree of correlation between two SNPs, is indicated by the number in the cell. Different numbers of common (frequency ≥5%) haplotypes were identified in each haplotype block. A modified Gabriel et al. algorithm was used to define the haplotype block , .
Figure 2
Figure 2. Postulated mechanism for CHRNA7 polymorphisms and ChEI cognitive response.
ChEIs increase the level of acetylcholine, which binds to α7 nAChR (encoded by CHRNA7). CHRNA7 polymorphisms are postulated to affect the cognitive response to ChEIs through the following mechanisms: (1) modulation of neurotransmitter release in presynaptic neurons, (2) enhancement of memory via mediating cholinergic neurotransmission, (3) neuroprotection via α7 nAChR, (4) upregulation of α7 nAChR by ChEI, and (5) galantamine-associated positive allosteric modulation of α7 nAChR. Abbreviations: nAChR, nicotinic acetylcholine receptor; ACh, acetylcholine; ChE, cholinesterase; ChEI, cholinesterase inhibitor.
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References

    1. Coyle JT, Price DL, DeLong MR (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219: 1184–1190. - PubMed
    1. London ED, Ball MJ, Waller SB (1989) Nicotinic binding sites in cerebral cortex and hippocampus in Alzheimer's dementia. Neurochem Res 14: 745–750. - PubMed
    1. Taylor P (1998) Development of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease. Neurology 51: S30–35 discussion S65–37. - PubMed
    1. Lam B, Hollingdrake E, Kennedy JL, Black SE, Masellis M (2009) Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story. Hum Genomics 4: 91–106. - PMC - PubMed
    1. O'Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, et al. (2003) Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 13: 231–239. - PubMed

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Grants and funding

Funding for the study was provided by National Science Council grants 96-2314-B-002-197 and 97-2314-B-002-168-MY3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.