Imipramine binds to amyloid-β and extends the survival of Alzheimer's disease patients

Background Apolipoprotein E (apoE) plays numerous roles in the pathogenic pathway to Alzheimer's disease (AD). We previously performed a high-throughput screen and identified the antidepressant imipramine as an inhibitor of the interaction between apoE and amyloid-β (Aβ). We also found that imipramine use to treat depression in AD patients was associated with better Mini-Mental State Exam (MMSE) scores. Here we studied the mechanisms by which imipramine inhibits the AD pathogenic pathway and investigated its effect on mortality in AD patients. Methods Nuclear magnetic resonance spectroscopy was used to characterize the interaction between imipramine and Aβ monomers. Human induced pluripotent stem cell (hiPSC)-derived AD cerebral organoids (COs) and transgenic AD rats treated with imipramine underwent neuropathological evaluation, while rat learning and memory were assessed in the Morris Water Maze. AD patient mortality in the National Alzheimer's Coordinating Center's database was analyzed by Kaplan-Meier and Cox proportional hazards models. Results Imipramine inhibits the apoE-Aβ interaction by binding directly to Aβ monomers. Imipramine reduces Aβ accumulation and neuronal cell loss in AD COs. Imipramine-treated female AD rats had enhanced reference memory and increased hippocampal cellularity and cholinergic neurotransmission. AD patients prescribed imipramine had reduced all-cause mortality over 10 years relative to those prescribed other tricyclic antidepressants (TCA), non-TCA antidepressants, or no antidepressants. Conclusions The findings support the conclusions that: a) the mechanism by which apoE confers risk for AD is by catalyzing the polymerization of Aβ into neurotoxic species, b) targeting apoE is a promising, underappreciated strategy for the prevention of AD, c) imipramine should be used more frequently to treat depression in AD clinical practice, and d) imipramine should be evaluated in prospective trials, particularly in APOE4 carriers, as a potential method to improve cognition and reduce mortality in AD.