Impact of genetic variants in the longevity gene PPARGC1A and cerebrospinal fluid PPARγ levels on clinical trajectories in Parkinson's disease: Potential biomarkers for neurodegeneration and ageing.

INTRODUCTION

Parkinson's disease (PD) is characterized by marked phenotypic heterogeneity particularly with regard to cognitive decline, which may be partly driven by ageing-related molecular pathways. Peroxisome Proliferator-Activated Receptor γ (PPARγ) represents a key downstream component of such pathways, while genetic variation in its coactivator gene peroxisome proliferator-activated receptor γ coactivator-1-α (PPARGC1A) may further modulate disease trajectories. We aimed to investigate the association of cerebrospinal fluid (CSF) PPARγ levels and PPARGC1A single nucleotide polymorphisms (SNPs) with clinical outcomes in PD,

METHODS

CSF PPARγ levels were measured in a cohort of 446 with PD, 61 patients with dementia with Lewy Bodies (DLB), and 13 control participants. Associations with clinical parameters were analyzed using cross-sectional and longitudinal approaches. In addition, three PPARGC1A SNPs (rs4697447, rs7659588, rs4697455) were examined for their relationship with cognitive and motor outcomes.

RESULTS

Higher CSF PPARγ levels were associated with older age at examination and lower Montreal Cognitive Assessment (MOCA) scores. PPARγ levels differed across diagnostic groups, with highest levels observed in DLB, followed by PD and controls. Elevated PPARγ levels were associated with a higher incidence of cognitive impairment; these associations were largely attenuated after adjustment for age. In exploratory analyses, PPARGC1A variants were associated with cognitive trajectories.

CONCLUSION

CSF PPARγ levels are primarily associated with ageing-related processes rather than reflecting disease-specific effects. Genetic variation in PPARGC1A may contribute to interindividual differences in cognitive progression. Together, these findings support a role of ageing-related pathways in shaping clinical heterogeneity in PD.