Objective: To investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in both striatal dopaminergic denervation and the development of dementia in Parkinson’s disease (PD).

Background: The dual syndrome hypothesis for cognitive impairment in PD was recently proposed, establishing a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to cognitive decline in PD, and the exact contribution of these genes to each syndrome is still a matter of debate.

Methods: We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. [123I]FP-CIT SPECTs from these patients were collected and the percentage of age-expected ligand uptake in putamen and caudate were calculated. The association between imaging and genetic parameters was investigated through linear regression with PLINK. A long-term review (mean disease duration 11 years) was performed to ascertain the presence and onset of dementia based on established criteria, and its relationship with the genetic factors was studied by Cox regression survival analyses.

Results: We found that the APOE2 allele (Pput=0.002; Pcau=0.012), the minor allele ‘G’ in SNCA polymorphism (Pput=0.018; Pcau=0.006) and variants in GBA (Pput=0.029; Pcau=0.019) all had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau=0.026). Further, the development of dementia was influenced by the APOE4 allele (HR=1.85; P=0.04) and variants in GBA (HR=2.06; P=0.03). MAPT had no role in either striatal degeneration or dementia.

Conclusions: APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia. This suggests that GBA may be related to both dopaminergic and non-dopaminergic mechanisms of degeneration. Our results appear to indicate that the dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-factors-influencing-frontostriatal-dysfunction-and-the-development-of-dementia-in-parkinsons-disease/