{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Several large‐scale genetic studies have examined the role of the EXOC3L2 locus in late‐onset Alzheimer’s disease (AD). Initial genome‐wide association analyses detected a single nucleotide polymorphism (rs597668) near EXOC3L2 that reached genome‐wide significance as a potential risk factor for AD"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", although other studies subsequently reported that the observed association was not independent of the well‐established APOE ε4 effect."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " In particular, analyses in different populations—including those of Asian descent—suggest that the implicated risk allele at EXOC3L2 may exhibit variable effects or even lack a major independent contribution to AD susceptibility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In a complementary line of investigation, functional studies on EXOC3L2 in vascular biology have revealed that the gene—encoding a component of the exocyst complex involved in vesicular trafficking—plays an important role in endothelial cell function. In endothelial cells, EXOC3L2 mRNA is up‐regulated in response to VEGFA, and the protein interacts with other exocyst components (such as EXOC4 and EXOC7). Loss‐of‐function studies demonstrate that silencing EXOC3L2 reduces VEGF receptor 2 phosphorylation and impairs VEGFA‐directed migration, thereby implicating EXOC3L2 in angiogenic signaling and vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, although genetic analyses have provided mixed evidence regarding an independent association of EXOC3L2 with AD risk—likely due to confounding by APOE ε4—the gene itself appears to have a clear functional role in modulating exocyst-dependent vesicle targeting and VEGFA signaling in endothelial cells. These findings suggest that EXOC3L2 may contribute to disease pathophysiology through vascular mechanisms even as its role as an AD susceptibility locus remains to be fully clarified.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Adam C Naj, Gyungah Jun, Gary W Beecham, et al. 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