AbstractAlzheimer’s disease (AD) is an irreversible neurodegenerative disorder that affects millions of people worldwide. AD pathogenesis is intricate. It primarily involves two main molecular players—amyloid-β (Aβ) and tau—which actually have an intrinsic trend to generate molecular assemblies that are toxic to neurons. Incomplete knowledge of the molecular mechanisms inducing the onset and sustaining the progression of the disease, as well as the lack of valid models to fully recapitulate the pathogenesis of human disease, have until now hampered the development of a successful therapy for AD. The overall experience with clinical trials with a number of potential drugs—including the recent outcomes of studies with monoclonal antibodies against Aβ—seems to indicate that Aβ-targeting is not effective if it is not accompanied by an efficient challenge of Aβ neurotoxic properties. We took advantage from the discovery of a naturally-occurring variant of Aβ (Aβ_A2V) that has anti-amyloidogenic properties, and designed a novel bio-inspired strategy for AD based on the intranasal delivery of a six-mer peptide (Aβ1-6_A2V) retaining the anti-amyloidogenic abilities of the full-length Aβ_A2V variant. This approach turned out to be effective in preventing the aggregation of wild type Aβ and averting the synaptic damage associated with amyloidogenesis in a mouse model of AD. The results of our preclinical studies inspired by a protective model already existing in nature, that is the human heterozygous Aβ_A2V carriers which seem to be protected from AD, open the way to an unprecedented and promising approach for the prevention of the disease in humans.