Age-Related Association Between APOE epsilon 4 and Cognitive Progression in de novo Parkinson's Disease

Background: APOE epsilon 4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson's disease (PD). Meanwhile, the differential influence of APOE epsilon 4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. Objective: To examine whether the effect of APOE epsilon 4 on cognitive progression in de novo PD is age dependent. Methods: In this study, 613 de novo PD patients were recruited from Parkinson's Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE epsilon 4 and cognitive changes, we added 3-way interaction of APOE epsilon 4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE epsilon 4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants. Results: Age significantly modified relationship betweenAPOE epsilon 4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE epsilon 4 carriers showed steeper decline in global cognition (p = 0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143-2.310, p = 0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE epsilon 4 and cognitive decline can be detected. Conclusion: Our results indicated that the APOE epsilon 4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.