Abstract
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 evidence to suggest that CypA or MMP9 affects the risk of Alzheimer’s 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 human APOE4 carriers.
Highlights
Therapeutic targets for halting the progression of Alzheimer’s disease pathology are lacking
We found little evidence to suggest APOE4 has a causal effect on circulating CypA or MMP9 eQTLs or pQTLs using two-sample Mendelian randomization
We found very little genomic support for CypA as a promising therapeutic target for cognitive impairment in human APOE4 carriers
Summary
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. We found little evidence to suggest that CypA or MMP9 affects the risk of Alzheimer’s 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 human APOE4 carriers. Studies have reported that blockade of the CypA–MMP9 pathway in APOE4 knock-in mice restores blood brain barrier integrity and subsequently normalises neuronal and synaptic function[2]. We aimed to triangulate the existing evidence for the causal effect of CypA and MMP9 on cognitive impairment from experimental studies, with evidence from two-sample Mendelian randomization and polygenic risk score analysis in humans, to examine whether CypA and MMP9 are likely to be effective drug targets for cognitive impairment in human APOE4 carriers
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