IMPACT OF APOE GENOTYPE AND CSF BIOMARKERS OF AD CO-PATHOLOGY ON COGNITIVE DECLINE AND MOTOR PROGRESSION IN SPORADIC, GBA, AND LRRK2 PARKINSON'S DISEASE

Abstract

Parkinson’s disease (PD) is emerging as rapidly escalating global health problem. As of 2019, an estimated 8.5 million individuals worldwide are affected, with prevalence doubling over 25 years. Disability-adjusted life years (DALYs) linked to PD have risen, alongside a 100% mortality increase since 2000. This growing burden—marked by rising incidence, prevalence, morbidity, and mortality—necessitates refining our understanding of PD clinical heterogeneity, especially in genetic subtypes, which account for 10–15% of cases. Emerging evidence underscores the significance of Alzheimer’s disease (AD) co-pathology in PD, raising questions about its impact on progression. The APOE genotype, particularly the APOE4 allele, a known AD risk factor, may also influence PD progression. While cognitive decline is a key non-motor PD feature, the role of APOE4 in motor deterioration is underexplored, and its effect on cognitive decline shows mixed results. Additionally, whether APOE4 affects sporadic and genetic PD subtypes differently, especially LRRK2-associated PD, is a critical gap. The role of AD-associated CSF biomarkers in PD also needs further study. The classical AD signature—low Aβ42 and elevated phosphorylated tau (pTau) in CSF —may be linked to worsened cognitive decline in PD. However, it is unclear if this biomarker profile affects all PD subtypes or shows subtype-specific effects. Understanding these factors is crucial for enrichment strategies in disease-modifying trials. Identifying biomarker-defined subgroups with accelerated progression can better enrich trials for patients likely to benefit from targeted interventions. This approach is essential, as PD remains incurable, and precision-based therapeutic strategies are urgently needed. Using longitudinal multicenter data, in manuscript 1, we studied the impact of APOE polymorphism and CSF AD biomarkers on the cognitive trajectories of sporadic, genetic PD and Healthy control groups and in manuscript 2, we analyzed the impact of APOE polymorphism on the motor decline in sporadic and genetic PD groups. This body of work, based on two longitudinal cohort studies, highlights the differential impact of APOE polymorphisms and AD co-pathology markers on cognitive decline and motor progression in sporadic and genetic PD (GBA-PD, LRRK2-PD). In the first study, APOE ε4 carriers in sPD experienced significantly faster cognitive decline compared to ε3 and ε2 carriers, a pattern not observed in GBA-PD, LRRK2-PD, or healthy controls. Regarding CSF biomarkers of AD co-pathology, lower Aβ42 levels universally predicted cognitive decline across all groups, whereas higher baseline p-tau levels were linked to worse cognitive outcomes in sPD and LRRK2-PD, but not in GBA-PD or HC. The second study assessed motor progression in relation to APOE polymorphisms across PD subtypes, revealing that APOE ε4 carriers in sPD exhibited faster motor decline compared to ε3 carriers, while no such association was found in genetic PD subtypes. These findings emphasize the importance of genotyping PD patients not only for GBA and LRRK2 variants but also for APOE polymorphisms, as APOE’s impact on disease progression differs between sporadic and genetic PD. With growing recognition of AD co-pathology in PD and PD-related changes in AD, it is essential to understand how these overlapping pathologies shape the clinical trajectory. This knowledge is critical for designing future clinical trials on disease-modifying therapies and calls for large-scale, longitudinal studies to further validate these differential effects.