Genetic risk factors for cognitive decline in Parkinson's disease: a review of the literature.

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Parkinson's disease is a highly heterogeneous disorder, where genetic factors are likely to contribute to clinical variability, including susceptibility to cognitive impairment and dementia. Monogenic forms of parkinsonism show distinct cognitive profiles, yet less is known about the impact of common genetic variants on cognition in sporadic Parkinson's disease. In a systematic review of the literature, the current results from genetic association studies of cognitive outcomes are summarized and prospects and challenges for future studies are discussed. Literature searches of the PubMed database were performed and studies using statistical methods to assess associations between genetic variation and any cognitive outcome in Parkinson's disease patients were included. For each of the candidate loci investigated in several studies, the current evidence is summarized and discussed. Sixty-one articles meeting our inclusion criteria were identified, which were highly heterogeneous with respect to study design, size and cognitive outcome measures. GBA mutations have a negative impact on cognition, whereas LRRK2-associated disease may have a milder cognitive phenotype than idiopathic Parkinson's disease. For common variants, reported results are partly conflicting, even across the larger studies, with some evidence to suggest a potential effect of APOE, MAPT, COMT and SNCA on cognitive outcomes. Future investigations should aim to collect high-quality cognitive data in a standardized way that allows for direct comparison across studies and large-scale meta-analysis. Linking genetic profiles to cognitive outcomes may have an important clinical impact, facilitating the stratification of patients for clinical trials and, ultimately, individualized treatment in Parkinson's disease.

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