Netrin-1 as a molecular mediator linking APOE ε4 to alzheimer’s disease pathogenesis

The ɛ4 allele of the apolipoprotein E (APOE) gene stands as the most significant genetic risk factor for Alzheimer's disease (AD), although the underlying mechanism linking APOE to the disease remains elusive. Netrin-1, has been found to inhibit Aβ production, reduce neuroinflammation, and regulate synaptic plasticity, thereby playing a role in AD. Recent reports suggest that Netrin-1 could be a key protein connecting APOE ɛ4 with Aβ and tau tangles. This study aims to investigate whether APOE regulates the expression or function of Netrin-1, thus influencing the risk of developing AD. The serum levels of Netrin-1 were notably reduced in patients with AD compared to healthy individuals, whereas interleukin-6 (IL-6) concentrations were higher in the AD group. patients harboring the APOE ε4 allele exhibited a more pronounced decrease in Netrin-1 compared to those with other APOE genotypes. Furthermore, a correlation was observed between Netrin-1 concentrations and APOE allelic variations. Our results imply that Netrin-1 is a key player in the cognitive decline observed in AD and potentially contributes to the APOE-driven cognitive impairment process. This association is tightly linked to inflammatory factors, suggesting that Netrin-1 may serve as a crucial biomarker for the prognosis and therapeutic intervention of AD.