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The  dual syndrome  hypothesis for cognitive impairment in Parkinson's disease (PD) establishes 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 these syndromes although the exact contribution is still controversial. The study’s objective was to investigate the role of  APOE ,  MAPT ,  COMT ,  SNCA  and  GBA  genes in the dual syndromes. 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. The degree of dopaminergic depletion was investigated with [ 123 I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that  APOE2  allele ( P   put   = 0.002;  P   cau   = 0.01), the minor allele 'G' in  SNCA  polymorphism ( P   put   = 0.02;  P   cau   = 0.006) and  GBA  deleterious variants in ( P   put   = 0.01;  P   cau   = 0.001) had a detrimental effect on striatal [ 123 I]FP-CIT uptake in PD. Conversely, Met/Met carriers in  COMT  polymorphism had increased caudate uptake ( P   cau   = 0.03). The development of dementia was influenced by  APOE4  allele (HR = 1.90;  P  = 0.03) and  GBA  deleterious variants (HR = 2.44;  P  = 0.01). Finally, we observed no role of  MAPT  locus in any of the syndromes. As a conclusion,  APOE2 ,  SNCA ,  COMT  and  GBA  influence frontostriatal dysfunction whereas  APOE4  and  GBA  influence the development of dementia, suggesting a double-edged role of  GBA . The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease