Re-thinking Alzheimer's disease therapeutic targets using gene-based tests

Background: Alzheimer's disease (AD) is a devastating condition with no known effective drug treatments. Existing drugs only alleviate symptoms. Given repeated expensive drug failures, we assessed systematically whether approved and investigational AD drugs are targeting products of genes strongly associated with AD and whether these genes are targeted by existing drugs for other indications which could be re-purposed. Methods: We identified genes strongly associated with late-onset AD from the loci of genetic variants associated with AD at genome-wide-significance and from a gene-based test applied to the most extensively genotyped late-onset AD case (n = 17,008)-control (n = 37,154) study, the International Genomics of Alzheimer's Project. We used three gene-to-drug cross-references, Kyoto Encyclopedia of Genes and Genomes, Drugbank and Drug Repurposing Hub, to identify genetically validated targets of AD drugs and any existing drugs or nutraceuticals targeting products of the genes strongly associated with late-onset AD. Findings: A total of 67 autosomal genes (forming 9 gene clusters) were identified as strongly associated with late-onset AD. 28 from the loci of single genetic variants, 51 from the gene-based test and 12 by both methods. Existing approved or investigational AD drugs did not target products of any of these 67 genes. Drugs for other indications targeted 11 of these genes, including immunosuppressive disease-modifying anti-rheumatic drugs targeting PTK2B gene products. Interpretation: Approved and investigational AD drugs are not targeting products of genes strongly associated with late-onset AD. However, other drugs targeting products of these genes exist and could perhaps be repurposing to combat late-onset AD after further scrutiny. (C) 2018 The Authors. Published by Elsevier B.V.