Age-Related Association Between APOE ɛ4 and Cognitive Progression in de novo Parkinson’s Disease

Background: APOE ɛ4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson’s disease (PD). Meanwhile, the differential influence of APOE ɛ4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. Objective: To examine whether the effect of APOE ɛ4 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 ɛ 4 and cognitive changes, we added 3-way interaction of APOE ɛ4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ɛ4 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 between APOE ɛ4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ɛ4 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 ɛ4 and cognitive decline can be detected. Conclusion: Our results indicated that the APOE ɛ4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.