Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer's disease cognition

The apolipoprotein E (APOE) {varepsilon}4 allele confers the strongest risk for late-onset Alzheimers disease (AD) besides age itself, but the mechanism(s) underlying this risk are debated. The critical test of any proposed AD mechanism is whether it leads to effective treatments. We developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of the amyloid {beta} (A{beta}) peptide into neurotoxic fibrils. Screening a human drug library, we identified five non-toxic, blood-brain-barrier-permeable hit compounds that reduced apoE4-promoted A{beta} and tau neuropathology in cultured neurons. Two hit compounds, imipramine and olanzapine, but not other (non-hit) antipsychotics or antidepressants, when prescribed to AD patients for their normal clinical indications, led to improvements in cognition and clinical diagnosis. Imipramine and olanzapine have no structural, functional, or clinical similarities other than their ability to inhibit apoE4-catalyzed A{beta} polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD. One Sentence SummaryHigh-throughput drug screens, studies in Alzheimers disease cell culture models, and analyses of human clinical data identified inhibitors of the apoE4-A{beta} interaction as a novel class of Alzheimers disease therapeutics.