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

Abstract

AbstractBackgroundApolipoprotein E-ε4 (APOEε4) 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.ObjectivesIn the current work we aimed to assess the impact ofAPOEgenotype on cognition in iPD as well as in genetic PD with mutations in theAlpha-synuclein(SNCA) andGlycocerebrosidase(GBA1) genes.MethodsTwo independent PD cohorts were analyzed: The first cohort (Athens) included 50 iPD patients, 35 patients with the p.A53TSNCAmutation and 59 patients withGBA1mutations (13 mild /46 severe). The second cohort (Tübingen) included 292 patients withGBA1mutations (170 risk/ 52 mild/ 70 severe). All patients underwent cognitive testing and were genotyped forAPOE.ResultsIn the iPD subgroup, carriers of at least oneAPOEε4 exhibited lower Montreal Cognitive Assessment test (MoCA) score as compared to non-carriers (p=0.044). Notably, in the p.A53TSNCAsubgroup,APOEε4 carriers also had lower MoCA scores compared to non-carriers (p=0.039). There were noAPOEε4-related differences in the twoGBA1subgroups (Athens, p=0.729; Tübingen p=0.585).ConclusionsWe confirm the impact ofAPOEε4 on cognitive decline in iPD and for the first time report a similar effect in p.A53TSNCAmutation carriers, who represent the prototypical genetic synucleinopathy. Contrary, the lack of such an effect in two independent cohorts ofGBA1mutation 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.