In this study, we investigated the relationship between Shank3 deficiency, cognitive impairment, as well as Aβ and tau neuropathologies in brain samples from the Religious Orders Study and in hemizygous 3xTg-AD mice lacking one Shank3 allele (Shank3Δex4-9), assessed at different ages. The gene discussed is MAPT; the disease is Alzheimer disease.