Identification of small molecule drugs that target apolipoprotein E4‐catalyzed amyloid‐β fibrillization: A new therapeutic approach to Alzheimer’s disease

Abstract

AbstractBackgroundCarrying the ε4 allele of the apolipoprotein E (APOE) gene is the strongest risk factor for Alzheimer’s disease (AD) besides age itself. Having one copy of APOE4 triples the risk for AD, whereas being homozygous for APOE4 increases the risk by greater than 12‐fold. As one potential mechanism, apoE, and especially apoE4, acts as a catalyst to accelerate the polymerization rate of amyloid‐β (Aβ) into neurotoxic oligomers and filaments. Thus, inhibiting this catalytic process is a promising therapeutic approach to preventing AD. Repurposing a known drug to inhibit the apoE4‐Aβ interaction would have numerous benefits such as faster, less expensive testing in clinical trials, and a greater chance of making it to market.MethodWe developed an apoE4‐Aβ fibrillization assay and screened two small molecule drug repurposing libraries containing more than 3,000 compounds with a history of use in human clinical trials. The cytotoxicity and efficacy of hit compounds were evaluated in transgenic mouse and rat primary neurons. We also modeled changes in cognition using MMSE scores and clinical diagnoses of National Alzheimer’s Coordinating Center (NACC) participants using time slopes and Cox proportional hazards, respectively, and adjusted for age and sex.ResultOur high‐throughput screen identified 31 hit compounds that inhibited apoE4‐catalyzed Aβ fibrillization in a dose‐dependent manner. Five of those hit compounds were non‐toxic, blood‐brain barrier permeable, and reduced apoE4‐induced Aβ and tau neuropathology in AD cell culture models. One hit compound was the anti‐depressant imipramine, which, when taken by AD patients, was associated with improved cognition (P=0.0490) and increased incidence of receiving an improved clinical diagnosis (P<0.0001), compared to all other anti‐depressants. Another hit compound was the anti‐psychotic olanzapine, which, when taken by AD patients who were APOE4 carriers, was associated with improved cognition (P=0.0235) and improved clinical diagnosis (P=0.0435), compared to all other anti‐psychotics.ConclusionWe identified five novel inhibitors of the apoE4‐Aβ interaction, two of which were associated with clinical improvements when prescribed to AD patients for their normal indications. These findings validate an apoE‐centric approach to developing new AD therapeutics. This set of small molecules may be useful for preventing or reversing AD, particularly in APOE4 carriers.