The general aim of the proposed study is to validate the endocannabinoid Palmithoylethanolamide (PEA) as a clinical candidate for Alzheimer's Disease (AD) therapy. To this aim, we intend to verify whether chronic (3 months) PEA treatments are able to prevent/slow the age-dependent progression of the pathology in a transgenic animal model of AD [the triple-transgenic murine model of AD (3xTg-AD)]. We also intend to identify an optimal PEA dose and to compare preventive vs therapeutic pharmacological interventions with PEA in AD. To these purposes, presymptomatic (2-3 months of age) and symptomatic (12 months of age) 3xTg-AD mice will be used. The project aims will be accomplished by complementary in vitro and in vivo approaches focusing on age-dependent neuroinflammation (panel of cytokines/chemokines), synaptic dysfunction (acetylcholine and glutamate levels by in vitro synaptosome experiments; synaptophysin and PSD-95 protein levels) and cognitive performances (novel object recognition test, Y-maze test, Barnes maze test). For translational purposes, we intend to administer PEA by oral gavage to the mice and to also define the pharmacokinetic profile of the compound.We anticipate that due to its anti-inflammatory and neuroprotective profile along with its safety properties in humans, PEA is a good candidate as disease-modifying drug in AD.