Genetically prioritized druggable targets for amyloid-β pathology highlight ACE as a therapeutic candidate in Alzheimer's disease

초록

Background Alzheimer's disease (AD) is characterized by a neuropathological cascade that begins with amyloid-beta (A beta) deposition. The recent success of disease-modifying drugs targeting A beta has demonstrated that modulating amyloidopathy can yield clinical benefits, underscoring the need for additional drugs affecting amyloid pathology. Objective: To identify novel drug targets associated with A beta accumulation in AD using Mendelian randomization (MR) analysis of the druggable genome. Methods: We performed MR analysis on expression quantitative trait loci (eQTLs) of the druggable genome in relation to A beta accumulation using summary-data-based MR (SMR). Blood eQTL data were obtained from the eQTLGen consortium, and brain eQTL data from BrainMeta and PsychENCODE, while A beta positron emission tomography (PET) genome-wide association study data were derived from 11,816 non-Hispanic White participants across 13 cohorts. Co-localization analysis was conducted to enhance the reliability of the MR results, and additional validation was performed using blood and brain protein quantitative trait loci (pQTLs) as instrumental variables. Results: The SMR and co-localization analyses revealed causal associations between the druggable genome and A beta accumulation, with APH1B identified in blood eQTL data and ACE, APH1B, and CR1 identified in brain eQTL data. Further analysis using pQTL data confirmed causal associations for ACE and CR1, with ACE showing a negative association with A beta PET uptake. Conclusions: These findings highlight potential target genes for AD treatment, and the protective effect of ACE against amyloid pathology suggests that alternative medications to ACE inhibitors may be preferred for blood pressure management in the context of AD. Overall, our study demonstrates the potential of MR to facilitate drug repurposing for AD.

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