COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

Porter, Tenielle; Burnham, Samantha; Milicic, Lidija; Savage, Greg; Maruff, Paul; Sohrabi, Hamid R.; Peretti, Madeline; Lim, Yen Ying; Weinborn, Michael; Ames, David; Masters, Colin L.; Martins, Ralph N.; Rainey-Smith, Stephanie R.; Rowe, Christopher C.; Salvado, Olivier; Groth, David; Verdile, Giuseppe; Villemagne, Victor L.; Laws, Simon M.

doi:10.1016/j.ibror.2019.05.001

Cited by 5 publications

(4 citation statements)

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“…Val allele (G allele) in COMT gene that results in lower dopamine levels in synaptic cleft was associated with increased risk for AD [47]. COMT Val158Met polymorphism was compared with genetic biomarkers of AD, such as apolipoprotein E (APOE) [48][49][50][51], and with neuroimaging biomarkers of AD [52][53][54]. However, the association of COMT Val158Met polymorphism with CSF AD biomarkers was not previously tested, and case-control studies on association of COMT Val158Met polymorphism and AD yielded incon-sistent results.…”

Section: Discussionmentioning

confidence: 99%

Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

Leko

Perković

Klepac

et al. 2020

JAD

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The noradrenergic and dopaminergic systems are affected in Alzheimer's disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine ␤hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called -1021C/T or -970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau 181 , p-tau 199 , and p-tau 231 ), amyloid-␤ 42 (A␤ 42 ), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in A␤ 42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau 181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. A␤ 42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau 181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

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Section: Discussionmentioning

confidence: 99%

Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

Leko

Perković

Klepac

et al. 2020

JAD

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“…AIBL has contributed to the understanding of how individual genes [47,67,76,77,[111][112][113][114][115] make variable contributions to cognitive decline in the preclinical and prodromal stages of AD. This has been extended to enhanced understanding of accumulative genetic contributions and whether genetic profiles for risk and progression differ.…”

Section: Geneticsmentioning

confidence: 99%

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

Fowler¹,

Rainey‐Smith²,

Bird³

et al. 2021

ADR

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Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

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“…Dennis et al reported that COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals but has an impact on neural activation patterns. Beyond that, Porter et al (2019) found no previous associations between COMT Val158Met and cognitive performance in the cohort of cognitively normal older adults. In PD, many similar explorations focusing on genetic factors in cognitive decline were also made.…”

Section: Introductionmentioning

confidence: 66%

Meta-Analysis of the Effects of the Catechol-O-Methyltransferase Val158/108Met Polymorphism on Parkinson’s Disease Susceptibility and Cognitive Dysfunction

et al. 2019

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Background: There is a continued debate and inconsistent findings in previous literature about the relationship of catechol-O-methyltransferase (COMT) and Parkinson’s disease (PD) susceptibility as well as cognitive dysfunction. To substantiate this existing gap, we comprehensively examine COMT genotype effects on the development of PD and test the hypothesis that the Met158 allele of the COMT gene is associated with cognitive dysfunction by conducting a meta-analysis review. Methods: PubMed/MEDLINE, Embase, Cochrane databases search (18/30/08) yielded 49 included studies. Data were extracted by two reviewers and included COMT genotype, publication year, diagnostic status, ancestry, the proportion of male participants, and whether genotype frequencies were consistent with Hardy–Weinberg equilibrium. Unadjusted odds ratios (ORs) were used to derive pooled estimates of PD risk overall and in subgroups defined by ethnicity, gender, and onset of disease. Moreover, the association of certain cognitive domains in PD and COMT gene type was explored. Meta-analyses were performed using random-effect models and p value–based methods. All statistical tests were two-sided. The present study was registered with PROSPERO (CRD42018087323). Results: In the current studies, we found no association between COMT Val158/108Met polymorphism and PD susceptibility. However, the gender-stratified analyses revealed marginally significant effects in heterozygote model analyses in women ( P = 0.053). In addition, stratification according to onset of PD also shows significant effects of COMT Val158/108Met polymorphism on late-onset population both in recessive ( P = 0.017) and allelic ( P = 0.017) genetic models. For the intelligence quotient (IQ) score and Unified Parkinson Disease Rating Scale III (UPDRS III), there was no evidence for genetic association, except in subgroup analyses in Asian populations (IQ score, P = 0.016; UPDRS III, P < 0.001). Conclusion: The COMT Val158/108Met polymorphism is associated with the risk for PD in female or late-onset PD. Methionine/methionine carriers of Asian population performed significantly worse than the valine allele carriers in IQ score and UPDRS III.

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COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

Abstract: Highlights Effect of COMT Val158Met on cognitive decline in preclinical AD investigated. Impact on Aβ-amyloid and APOE ε4 mediated decline assessed. COMT does not influence Aβ-amyloid or APOE ε4 driven cognitive decline.

Cited by 5 publications

References 61 publications

Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

Meta-Analysis of the Effects of the Catechol-O-Methyltransferase Val158/108Met Polymorphism on Parkinson’s Disease Susceptibility and Cognitive Dysfunction

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