Alzheimers disease (AD) is the primary cause of dementia in the rapidly growing elderly population, thereby posing a significant healthcare challenge. Indeed, despite of the recent approval of new drugs, to date AD has no curative treatment. In response to this problem, the investigation on an alternative therapeutic approach, focused on protective factors against AD, is gaining ground. Consequently, the identification of the genetic and environmental basis of cognitive resilience provides the opportunity not only to unveiling the mechanisms underlying this disease but also and most important, to identify innovative therapeutic strategies. In this context, we evaluated the efficacy of two therapeutic interventions based on a lifestyle modification and a genetic protective factor. Specifically, on one side we demonstrated that the dietary DHA supplementation is capable of generating beneficial, albeit modest, effects in a preclinical AD model. On the other hand, we validated that a gene therapy involving PLA2G4E completely restores normal cognition in a 3rd generation AD mouse model. We then proceeded to delve into the mechanisms underlying the therapeutic effect of PLA2G4E. We explored the role of this enzyme in neuronal and brain development by describing its physiological expression in both in vitro and in vivo models. We found that its peak expression is required during the critical period for synaptogenesis. Moreover, we assessed the effects of inhibiting PLA2G4E demonstrating that a reduction in dendritic arborization and spine density, ultimately affecting neuronal function in vitro. On the other hand, complete knockout mice lacking PLA2G4E exhibited relevant behavioral alterations, particularly in memory function. These deficits were successfully reversed by overexpressing this enzyme, furtherly supporting the efficacy of a PLA2G4E-based gene therapy and expanding its potential to all neurological disorders coursing with synaptic degeneration.