Paraoxonase 1 Gene Polymorphisms Do Not Influence the Response to Treatment in Alzheimer’s Disease

Klimkowicz-Mrowiec, A.; Marona, Monika; Spisak, Karolina; Jagiełła, Jeremiasz; Wołkow, Paweł; Szczudlik, Andrzej; Słowik, Agnieszka

doi:10.1159/000330343

Cited by 12 publications

(5 citation statements)

References 39 publications

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“…97 Multiple studies have addressed the association between PON1 polymorphisms and AD. 91,[98][99][100][101][102][103][104][105] In a study with 756 AD subjects, the authors found no association between the two major PON1 polymorphisms and AD in African Americans or Caucasians. 91 The authors conclude that either these functional PON1 polymorphisms are not associated with AD, or that the relative risk is small.…”

Section: 70-73mentioning

confidence: 93%

Paraoxonase 1 in neurological disorders

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Gugliucci

2013

Redox Report

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Paroxonase 1 displays multiple physiological activities that position it as a putative player in the pathogenesis of neurological disorders. Here we reviewed the literature focusing on the role of paraoxonase 1 (PON1) as a factor in the risk of stroke and the major neurodegenerative diseases. PON1 activity is reduced in stroke patients, which significantly correlates inversely with carotid and cerebral atherosclerosis. The presence of the R allele of the Q192R PON1 polymorphism seems to potentiate this risk for stroke. PON1 exerts peroxidase activities that may be important in neurodegenerative disorders associated with oxidative stress. PON1 is also a key detoxifier of organophosphates and organophosphate exposure has been linked to the development of neurological disorders in which acetylcholine plays a significant role. In Parkinson's disease most of the studies suggest no participation of either L55M or the Q192R polymorphisms in its pathogenesis. However, many studies suggest that the MM55 PON1 genotype is associated with a higher risk for Parkinson's disease in individuals exposed to organophosphates. In Alzheimer's disease most studies have failed to find any association between PON1 polymorphisms and the development of the disease. Some studies show that PON1 activity is decreased in patients with Alzheimer's disease or other dementias, suggesting a possible protective role of PON1. No links between PON1 polymorphisms or activity have been found in other neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis. PON1 is a potential player in the pathogenesis of several neurological disorders. More research is warranted to ascertain the precise pathogenic links and the prognostic value of its measurement in neurological patients.

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Section: 70-73mentioning

confidence: 93%

Paraoxonase 1 in neurological disorders

Menini

Gugliucci

2013

Redox Report

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“…Conversely, a study by Klimkowicz-Mrowiec found that neither the SNP on residue 192 nor the SNPs on residues 55 and 161 were associated with response to donepezil and rivastigmine in a Polish AD cohort (Klimkowicz-Mrowiec et al, 2011 ). Further studies are needed to elucidate whether PON-1 could be useful in predicting response to AChEI or not.…”

Section: Discussionmentioning

confidence: 95%

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

et al. 2022

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BackgroundThe mainstay of therapy for many neurodegenerative dementias still relies on acetylcholinesterase inhibitors (AChEI); however, there is debate on various aspects of such treatment. A huge body of literature exists on possible predictors of response, but a comprehensive review is lacking. Therefore, our aim is to perform a systematic review of the predictors of response to AChEI in neurodegenerative dementias, providing a categorization and interpretation of the results.MethodsWe conducted a systematic review of the literature up to December 31st, 2021, searching five different databases and registers, including studies on rivastigmine, donepezil, and galantamine, with clearly defined criteria for the diagnosis of dementia and the response to AChEI therapy. Records were identified through the string: predict*AND respon*AND (acetylcholinesterase inhibitors OR donepezil OR rivastigmine OR galantamine). The results were presented narratively.ResultsWe identified 1,994 records in five different databases; after exclusion of duplicates, title and abstract screening, and full-text retrieval, 122 studies were finally included.DiscussionThe studies show high heterogeneity in duration, response definition, drug dosage, and diagnostic criteria. Response to AChEI seems associated with correlates of cholinergic deficit (hallucinations, fluctuating cognition, substantia innominate atrophy) and preserved cholinergic neurons (faster alpha on REM sleep EEG, increased anterior frontal and parietal lobe perfusion after donepezil); white matter hyperintensities in the cholinergic pathways have shown inconsistent results. The K-variant of butyrylcholinesterase may correlate with better response in late stages of disease, while the role of polymorphisms in other genes involved in the cholinergic system is controversial. Factors related to drug availability may influence response; in particular, low serum albumin (for donepezil), CYP2D6 variants associated with reduced enzymatic activity and higher drug doses are the most consistent predictors, while AChEI concentration influence on clinical outcomes is debatable. Other predictors of response include faster disease progression, lower serum cholesterol, preserved medial temporal lobes, apathy, absence of concomitant diseases, and absence of antipsychotics. Short-term response may predict subsequent cognitive response, while higher education might correlate with short-term good response (months), and long-term poor response (years). Age, gender, baseline cognitive and functional levels, and APOE relationship with treatment outcome is controversial.

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“…al. previously demonstrated that PON1 gene polymorphisms do not influence the response to treatment in AD [51]. So far, no study has investigated the relationship between responsiveness to the PON2 gene and cholinergic therapy.…”

Section: Discussionmentioning

confidence: 98%

Association between human paraoxonase 2 protein and efficacy of acetylcholinesterase inhibiting drugs used against Alzheimer’s disease

et al. 2021

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Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and cardiovascular disease. Since cholinergic deficiency is closely linked with Alzheimer’s disease (AD) progression, acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with AD. However, there is a heterogenous response to these drugs and mostly the subjects do not respond to the treatment. Gene polymorphism, the simultaneous occurrence of two or more discontinuous alleles in a population, could be one of the important factors for this. Hence, we hypothesized that PON2 and its polymorphic forms may be hydrolyzing the AChEIs differently, and thus, different patients respond differently. To investigate this, two AChEIs, donepezil hydrochloride (DHC) and pyridostigmine bromide (PB), were selected. Human PON2 wildtype gene and four mutants, two catalytic sites, and two polymorphic sites were cloned, recombinantly expressed, and purified for in vitro analysis. Enzyme activity and AChE activity were measured to quantitate the amount of DHC and PB hydrolyzed by the wildtype and the mutant proteins. Herein, PON2 esterase activity and AChE inhibitor efficiency were found to be inversely related. A significant difference in enzyme activity of the catalytic site mutants was observed as compared to the wildtype, and subsequent AChE activity showed that esterase activity of PON2 is responsible for the hydrolysis of DHC and PB. Interestingly, PON2 polymorphic site mutants showed increased esterase activity; therefore, this could be the reason for the ineffectiveness of the drugs. Thus, our data suggested that the esterase activity of PON2 was mainly responsible for the hydrolysis of AChEI, DHC, and PB, and that might be responsible for the variation in individual response to AChEI therapy.

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Paraoxonase 1 Gene Polymorphisms Do Not Influence the Response to Treatment in Alzheimer’s Disease

Cited by 12 publications

References 39 publications

Paraoxonase 1 in neurological disorders

Paraoxonase 1 in neurological disorders

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

Association between human paraoxonase 2 protein and efficacy of acetylcholinesterase inhibiting drugs used against Alzheimer’s disease

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