ABSTRACT The vast majority of therapeutic interventions targeting Alzheimer's disease (AD) until now have focused on monotherapies to alter a single neuropathology. Unfortunately, all these approaches have failed to meet the clinical endpoint of significantly slowing or reversing cognitive decline in AD subjects. This emphasizes the urgent need for novel therapeutic interventions to reduce several AD neuropathologies simultaneously. Inflammation is pervasive to many neurological disorders, yet no clinical trial has demonstrated the efficacy of anti-inflammatory agents for AD. Our research group is particularly interested in drugs that lower both systemic and central inflammation aiming at preventing or slowing down the clinical progression of AD. Our most promising compound is the immunomodulator, anti-cancer agent lenalidomide, which is one of the very few pleiotropic agents that both lowers the expression of pro-inflammatory (e.g. TNFα, IL-6, IL-8), and increases the expression of anti-inflammatory cytokines (e.g. IL-10), to modulate both innate and adaptive immune responses. Capitalizing on our experience from a previous clinical trial with an analog and our animal data, in the current project we aim to test the central hypothesis that lenalidomide reduces AD-associated neuroinflammation and neuropathologies, which might result in improved cognitive performances. For this, we designed a Phase Ib-IIa, proof-of-mechanism, placebo-controlled clinical study on single and multiple domain amnestic MCI subjects administered 10 mg/day lenalidomide for 12 months. Because lenalidomide has never been tested in the context of AD, we will monitor carefully the safety and tolerability in MCI patients. To demonstrate the engagement of lenalidomide in study subjects, we will measure inflammatory markers in the periphery every 3 months. We will measure cognitive performance via MCI-sensitive tests. In addition, we will assess target engagement (CSF markers) at the completion of dosing. This is highly significant because, if successful, lenalidomide will become one of the very few compounds capable of lowering several neuropathological features associated with AD. Furthermore, the major advantage of lenalidomide is that the drug I already FDA-approved for cancer treatment, thus it could rapidly be repurposed in a Phase IIb study.