CLU rs11136000 Promotes Early Cognitive Decline in Parkinson's Disease

Abstract

Background The C allele of the rs11136000 genetic variant of the clusterin gene has been associated with increased risk of Alzheimer's disease. However, a comprehensive characterization of the role of this genetic variant in early cognitive deterioration in PD is lacking. Methods Using the Parkinson's Progression Markers Initiative database, we compared baseline and 5‐year cognitive performance between high‐risk and low‐risk clusterin genotypes. Results At baseline, recently diagnosed and drug‐naive de novo PD patients with the high‐risk clusterin genotype showed lower cognitive scores in memory and executive function tests. These differences were even higher at the 5‐year follow‐up, when they showed a higher prevalence of clinically diagnosed mild cognitive impairment or dementia. They also showed cortical thinning at baseline and increased annual thinning in frontal and posterior cortical regions. Discussion Our results provide evidence of this clusterin genotype promoting early cognitive deterioration in PD, but further research is needed to delineate the specific neurodegenerative pathways underlying this clinical association. © 2020 International Parkinson and Movement Disorder Society

HDL Accessory Proteins in Parkinson’s Disease—Focusing on Clusterin (Apolipoprotein J) in Regard to Its Involvement in Pathology and Diagnostics—A Review

“…Clusterin gene (CLU) has been identified as a susceptibility genetic locus for a lateonset AD by genome-wide association studies (GWASs) and a meta-analysis [181], prompting research on the potential utility of CLU as a prediction marker for other NDDs, including PD [182,183]. Gao et al [182] analyzed the distribution of rs11136000, a single-nucleotide polymorphism in the CLU gene, among 791 PD patients (of which 19% had dementia) and 1580 matched controls, reporting that carriers of both T alleles (TT as compared to CT and CC) had a lower PD risk with odds ratio (OR) = 0.71 (95% CI: 0.55-0.92).…”

“…The risk was greater for PDD (OR = 0.49, 95% CI: 0.27-0.91) than PD without dementia (OR = 0.81, 95% CI: 0.61-1.06). In a subsequent longitudinal study, Sampedro et al [183] demonstrated that high-risk naïve PD patients, defined as carriers of C allele (CC or CT), were more likely to develop mild cognitive impairment (PD with MCI) or dementia (PDD), with relative risk ratio (RR) = 1.91 (95% CI: 1.1-3.4). They also performed worse on various cognitive assessments, including the Symbol Digit Modality Test (SDMT), Hopkins Verbal Learning Test (HVLT), Benton Judgment of Line Orientation (BLJO), and Montreal Cognitive Assessment (MoCA) at baseline and/or at the 5-year follow-up.…”

Genetic Insights into the Impact of Complement in Alzheimer’s Disease

“…The C allele is also associated with the risk of mild cognitive impairment (MCI) and progression from MCI to AD [ 83 , 84 ]. The minor T allele shows a mild protective effect [ 85 ]; this SNP has also recently been shown to be associated with cognitive decline in Parkinson’s disease patients [ 86 ]. The rs9331888 risk SNP has been associated with low levels of plasma clusterin and linked to alternative splicing of the CLU gene [ 82 , 87 , 88 ].…”

Secreted Chaperones in Neurodegeneration

“…Single nucleotide polymorphisms in clusterin have also been linked to early cognitive decline in PD ( Gao et al, 2011 ; Sampedro et al, 2020 ). Clusterin has also been investigated as a potential therapeutic for PD.…”