Impact ofAPOEgenotype on cognition in idiopathic and genetic forms of Parkinson’s disease

Background Apolipoprotein E-ε4 ( APOE ε4) genotype may be associated with the development of cognitive decline in idiopathic Parkinson’s disease i(PD), however its effect in genetic PD is understudied. Objectives In the current work we aimed to assess the impact of APOE genotype on cognition in iPD as well as in genetic PD with mutations in the Alpha-synuclein ( SNCA ) and Glycocerebrosidase ( GBA1 ) genes. Methods Two independent PD cohorts were analyzed: The first cohort (Athens) included 50 iPD patients, 35 patients with the p.A53T SNCA mutation and 59 patients with GBA1 mutations (13 mild /46 severe). The second cohort (Tübingen) included 292 patients with GBA1 mutations (170 risk/ 52 mild/ 70 severe). All patients underwent cognitive testing and were genotyped for APOE . Results In the iPD subgroup, carriers of at least one APOE ε4 exhibited lower Montreal Cognitive Assessment test (MoCA) score as compared to non-carriers (p=0.044). Notably, in the p.A53T SNCA subgroup, APOE ε4 carriers also had lower MoCA scores compared to non-carriers (p=0.039). There were no APOE ε4-related differences in the two GBA1 subgroups (Athens, p=0.729; Tübingen p=0.585). Conclusions We confirm the impact of APOE ε4 on cognitive decline in iPD and for the first time report a similar effect in p.A53T SNCA mutation carriers, who represent the prototypical genetic synucleinopathy. Contrary, the lack of such an effect in two independent cohorts of GBA1 mutation carriers, who are thought to also manifest a predominant alpha-synuclein-driven cognitive decline, suggests differences in factors associated with cognitive dysfunction between different genetic forms of synucleinopathies.