Novel targets for the treatment and prevention of Alzheimer's disease in the European population, inspiration from amyloid beta and tau protein

Alzheimer's disease (AD) is a gradual neurodegenerative ailment that lacks any disease-modifying intervention. Our objective was to pinpoint pharmacological targets with a focus on amyloid beta (Aβ) and tau to treat and prevent AD in the European population. A proteome-wide Mendelian randomization (MR) analysis was carried out to estimate the associations between proteins and cerebrospinal fluid (CSF) Aβ-42 and phosphorylated Tau (p-Tau). We utilized colocalization and MR analysis to investigate whether the identified proteins were associated with the risk of AD. Additionally, we expanded our investigation to include non-AD phenotypes by conducting a phenome-wide MR analysis of 1646 disease traits based on the FinnGen and UK Biobank databases to explore potential side effects. We identified 11 proteins that were genetically associated with both CSF Aβ-42 and p-Tau levels. The genetically predicted levels of three proteins, GAL3ST2, POLR1C, and BIN1, were found to be associated with an increased risk of AD with high colocalization. In the phenome-wide MR analysis, two out of the three biomarkers were associated with at least one disease, except for GAL3ST2, which was not associated with any disease under the threshold of FDR <0.1. POLR1C was found to be associated with the most disease traits, and all disease associations with genetically inhibited BIN1 were protective. The proteome-wide MR investigation revealed 11 proteins that were associated with the level of CSF Aβ-42 and p-Tau. Among them, GAL3ST2, POLR1C, and BIN1 were identified as potential therapeutic targets for AD and warrant further investigation. © 2024 The Authors. Published by Elsevier Ltd.