Aggregation and deposition of â-Amyloid (Aâ) is associated with neurodegeneration and Alzheimer disease (AD). Aâ is generated by proteolysis of the Amyloid Precursor Protein (APP), a transmembrane protein with a receptor-like structure. App mutations that affect Aâ generation or predispose to its aggregation are pathogenic and conduce to early-onset genetic forms of AD. APP is also a molecular target for toxic Aâ-assemblies mediating neurodegeneration through activation of heterotrimeric Go protein. The histidine doublet at positions 657-658 on APP are critical for Go activation. Recently, a new mutation on App was found in a neurologically healthy individual from the African-Mandenka ethnic. The mutation promotes the substitution of a histidine 658 by a proline (APPH658P) and is considered not pathogenic, although it had not been experimentally analyzed. Here we characterized the APPH658P mutation in cellular models. We found that the mutation does not affect APP processing, or its ability to interact with toxic Aâ aggregates. Significantly, APPH658P is unable to promote Aâ-neurodegeneration in primary hippocampal neurons. Moreover, APPH658P acts as a dominant-negative that prevents Aâ-induced activation of Go by APPwt. Our data suggest that the Mandenka APP mutant could protect from AD-neurodegeneration to its carriers.