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

Abstract

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.

Predict cognitive decline with clinical markers in Parkinson’s disease (PRECODE-1)

“…Our model for prediction of CI in PD should, however, be further validated with a larger cohort of drug-naïve PD patients with a longer follow-up period, to permit a correct interpretation in clinical settings. Moreover, additional factors should be considered for future models which could contribute towards clinical outcomes and the prediction of cognitive decline including different genetic profiles which have been shown to play a role in the variability of cognitive outcomes and rates of decline (Fagan and Pilstrom 2017;Liu et al 2017). The inclusion of genetic profiles, into future predictive models of cognitive decline, could be important to facilitate the accurate stratification of PD patients for clinical trials striving towards tailored personalised therapeutic approaches.…”

Bilingualism Is Associated with a Delayed Onset of Dementia but Not with a Lower Risk of Developing it: a Systematic Review with Meta-Analyses

“…Only 147 participants (across mono-and bilinguals) were APOE ε4 carriers (Ljungberg et al, 2016). Of note, whether APOE ε4 increases the risk of vascular dementia (Rohn, 2014), frontotemporal dementia (Verpillat et al, 2002), dementia with Lewy bodies (Lovati et al, 2010), and Parkinson's disease (Fagan & Pihlstrøm, 2017) is unclear (Lovati et al, 2010). Therefore, adjustment for the APOE ε4 likely did not reach sufficient statistical power (Sham & Purcell, 2014) in this study (Ljungberg et al, 2016) and its clinical relevance to other dementia etiologies may have been limited (Lovati et al, 2010).…”

A comprehensive analysis of SNCA‐related genetic risk in sporadic parkinson disease

“…It is highly plausible that the great clinical heterogeneity observed across individual PD patients to some extent reflects differences in underlying genetic architecture, with potential relevance for treatment. [36][37][38] As an example, a recent study reported that the β2-adrenoreceptor is a regulator of SNCA, and that β2 agonist use is negatively associated with PD, suggesting clinical trials of these drugs as a potential neuroprotective therapy. 39 Showing that SNCArelated risk varies by more than 2-fold across quintiles, and that rare homozygotes for the maximum-risk haplotypes may carry 4-fold PD susceptibility compared to the general population, we suggest that patients in the highrisk end of this spectrum would be the most suitable for such clinical trials.…”