CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease

Weng, Pei-Hsuan; Chen, Jen‐Hau; Chen, Ta‐Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen‐Ching

doi:10.1371/journal.pone.0084059

Cited by 30 publications

(27 citation statements)

References 44 publications

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“…Acetylcholinesterase inhibitors (AEI), such as galantamine are frequently utilized for treatment of AD (Taylor, 1998). Women with AD carrying the polymorphism rs8024987 in intron 2 of CHRNA7 show improved cognitive symptoms with AEI (Weng et al, 2013). …”

Section: 0 Genetics Of Chrna7 and Chrfam7a In Mental Illnessesmentioning

confidence: 99%

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

et al. 2015

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The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer’s disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease.

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Section: 0 Genetics Of Chrna7 and Chrfam7a In Mental Illnessesmentioning

confidence: 99%

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

et al. 2015

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“…Furthermore, the stimulation of postsynaptic α7nAChR increases calcium influx and activates the intracellular signal transduction pathway, conferring neuroprotective effect by protecting neurons against Aβ toxicity 7 . In addition to disease prediction, our previous work has found that CHRNA7 polymorphisms may predict cognitive response to cholinesterase inhibitors and serve as a pharmacogenomic marker in LOAD treatment 39 .…”

Section: Discussionmentioning

confidence: 99%

CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking

Weng

Chen

et al. 2016

Sci Rep

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α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-β. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, apolipoprotein E (APOE) ε4 status and smoking on dementia risk. This case-control study recruited 254 late-onset Alzheimer’s disease (LOAD) and 115 vascular dementia (VaD) cases (age ≥65) from the neurology clinics of three teaching hospitals in Taiwan during 2007–2010. Controls (N = 435) were recruited from health checkup programs and volunteers during the same period. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among APOE ε4 non-carriers, CHRNA7 rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio = 0.29, 95% confidence interval = 0.13–0.64, P = 0.002). Similar findings were observed for carriers of GT haplotype in CHRNA7 block4. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. These findings help to understand dementia pathogenesis.

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“…The CHRNA7 gene is reported to encode α7 nAChR, one of the major nAChR subunits in the central nervous system (CNS), on chromosome 15q14 . In a retrospective study conducted in 233 patients with mild-to-moderate AD, the ratio of responders to non-responders with galantamine treatment was significantly higher in women with the SNP2 of CHRNA7 rs8024987 compared with female non-carriers (p<0.01) [ 80 ]. A similar difference was not observed in patients treated with other ChEIs, suggesting the involvement of the APL effect of galantamine through α7nAChR.…”

Section: Factors Affecting Clinical Response To Cheismentioning

confidence: 99%

Strategies for Continued Successful Treatment in Patients with Alzheimer’s Disease: An Overview of Switching Between Pharmacological Agents

Blesa

Toriyama

Ueda

et al. 2018

CAR

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Introduction: Alzheimer’s disease (AD) is the most common cause of dementia, characterized by a progressive decline in cognition and function. Current treatment options for AD include the cholines-terase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, as well as the N-methyl-D-aspartate receptor antagonist memantine. Treatment guidelines recommend the use of ChEIs as the standard of care first-line therapy. Several randomized clinical studies have demonstrated the benefits of ChEIs on cogni-tion, global function, behavior and activities of daily living. However, patients may fail to achieve sus-tained clinical benefits from ChEIs due to lack/loss of efficacy and/or safety, tolerability issues, and poor adherence to the treatment. The purpose of this review is to explore the strategies for continued successful treatment in patients with AD.Methods: Literature search was performed for articles published in PubMed and MEDLINE, using pre-specified search terms. Articles were critically evaluated for inclusion based on their titles, abstracts, and full text of the publication.Results and Conclusion: The findings of this review indicate that dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and also address issues such as lack/loss of effica-cy or safety/tolerability in patients with AD. However, well-designed studies are needed to provide robust evidence.

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CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease

Cited by 30 publications

References 44 publications

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking

Strategies for Continued Successful Treatment in Patients with Alzheimer’s Disease: An Overview of Switching Between Pharmacological Agents

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