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Little genomic support for cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers

By Emma L Anderson, Dylan M. Williams, Venexia M Walker, Neil M Davies

Posted 22 Apr 2021
medRxiv DOI: 10.1101/2021.04.22.21255729

Therapeutic targets for halting the progression of Alzheimers disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the cyclophilin A matrix metalloproteinase-9 (CypA MMP9) pathway in the cerebrospinal fluid, arguing that this led 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 evidence that CypA or MMP9 affected the risk of Alzheimers disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in APOE4 carriers.

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