biostudies-literatureAnderson ELEconomic and Social Research CouncilMedical Research Council1057https://www.ebi.ac.uk/biostudies/studies/S-EPMC8776806biostudies-literatureUnknown12(1)Therapeutic targets for halting the progression of Alzheimer's disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the Cyclophilin-A matrix metalloproteinase-9 (CypA-MMP9) pathway, leading to an accelerated breakdown of the blood-brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA-MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evideScientific reportsLittle genomic support for Cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers.PMC8776806MC_UU_00011/4ES/N000757/1MR/P014437/1MC_UU_00019/3MC_UU_00019/2Williams DMAnderson ELDavies NMWalker VMfalseLittle genomic support for Cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers.Therapeutic targets for halting the progression of Alzheimer's disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the Cyclophilin-A matrix metalloproteinase-9 (CypA-MMP9) pathway, leading to an accelerated breakdown of the blood-brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA-MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evide2022-01-01T00:00:00Z2022 Jan2026-05-08T16:45:24.876Z2022-02-11T15:51:04.817ZS-EPMC87768063505854710.1038/s41598-022-05225-8