APOE epsilon-4 allele and cytokine production in Alzheimer's disease

Objective: The APOE epsilon-4 allele has consistently emerged as a susceptibility factor for Alzheimer's disease (AD). Pro-inflammatory cytokines are detectable at abnormal levels in AD, and are thought to play a pathophysiological role. Animal studies have shown dose-dependent correlations between the number of APOE epsilon-4 alleles and the levels of pro-inflammatory cytokines. The aims of this study were to investigate the influence of APOE genotypes on TNF-α, IL-6, and IL-1β secreted by peripheral blood mononuclear cells (PBMC) from human patients with AD and to analyze the correlation between cytokine production and AD clinical features. Methods: Outpatients with AD (n=40) were clinically evaluated for cognitive decline (MMSE) and psychiatric symptoms (Cornell Scale for Depression in Dementia; Neuropsychiatric Inventory) and genotyped for APOE variants. PBMCs were isolated from the donors and used to assess spontaneous and PMA-stimulated secretion of TNF-α, IL-6, and IL-1β. Cytokine production was determined by immunoenzymatic assays (ELISA). Results: In comparison with their counterparts without APOE4, patients with at least one copy of the APOE epsilon-4 allele showed higher spontaneous ( p=0.037) and PMA-induced ( p=0.039) production of IL-1β after controlling for clinical variables. Significant correlations were reported between NPI scores (psychotic symptoms) and IL-6 production. Conclusion: These preliminary findings suggest the involvement of inflammatory response in the pathogenic effect of the APOE epsilon-4 allele in AD, although their replication in larger samples is mandatory. The modest correlations between pro-inflammatory cytokines released at peripheral level and AD features emphasizes the need for further research to elucidate the role of neuroinflammation in pathophysiology of AD.