The present investigation is consistent with the following conclusions: (1) lower levels of Shank3 are found in the parietal cortex of individuals with AD, correlating with cognitive decline and tau accumulation; (2) a specific Shank3a deficit on one allele can be replicated in an animal model of AD; (3) the partial Shank3a loss synergizes with Aβ and tau neuropathologies to induce impairment in object recognition and anxiety-like behavior; and (4) defects in Shank3a increase the concentrations of transgene-induced Aβ42 and tau in the cortex of 3xTg-AD mice. Here, MAPT is linked to Anxiety.