APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson’s disease

Cognitive impairment varies across sporadic Parkinson's disease (PD) and the common genetic subtypes glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) PD and is influenced by Apolipoprotein E (APOE) polymorphisms and Alzheimer's disease (AD) co-pathology. However, the effects of APOE genotype, Aβ42 and tau on cognitive decline across these PD subtypes remain unclear. Using pooled longitudinal data across the PPMI and CPP cohorts, we examined the effects of APOE genotype and cerebrospinal fluid (CSF) Aβ42 and tau on cognitive decline across sporadic PD, GBA1-PD, LRRK2-PD, and healthy control (HC) subjects. Whereas in sporadic PD the APOE ε4 allele was associated with faster cognitive decline than APOE ε3 or ε2 alleles, no APOE effect was observed in GBA1-PD or LRRK2-PD. While lower baseline CSF Aβ42 was linked to faster cognitive decline in all groups, higher baseline CSF pTau was associated with faster decline in sporadic PD and LRRK2-PD but not in GBA1-PD. These findings underscore differential vulnerabilities to APOE genotype and AD-related biomarkers among PD subtypes, a critical consideration for clinical trials targeting cognitive decline in PD.