The vast majority of clinical trials for Alzheimer's disease (AD) until now have employed a single drug to alter one of the neuropathologies associated with AD. 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 drugs to reduce several AD neuropathologies simultaneously. Inflammation is pervasive to many neurological disorders. Our research group is particularly interested in drugs that lower both peripheral and brain inflammation, aiming at preventing or slowing down the clinical progression of AD. Our most promising compound is the anti-cancer agent lenalidomide, which is one of the very few pleiotropic agents that modulates both inflammation enhancing and inflammation inhibitory molecules released by cells in the body. Capitalizing on our experience from a previous clinical trial with an analog compound and our animal data, in the current project we aim to study whether 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 clinical study on subjects suffering amnestic mild cognitive impairment (MCI) 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 that the drug modulates inflammation, we will measure inflammatory markers in the blood. We will also measure cognitive performance via MCI-sensitive tests. In addition, we will assess whether the drug regulates cerebrospinal fluid markers of AD at the completion of the trial. The major advantage of lenalidomide is that the drug is already FDA-approved, thus it could rapidly be used in a Phase IIb study if our project is successful.