Two histopathological hallmarks of Alzheimer’s disease (AD), the tau rich neurofibrillary tangles and the senile plaques, predominating in amyloid-β (Aβ), have fueled research in distinct directions. Evidence suggests that Aβ triggers imbalanced activities of protein phosphatases and kinases thus affecting the phosphorylation state of tau in AD. The amyloid-β protein precursor (AβPP) itself appears to be hyperphosphorylated at different residues in AD brains, including at Thr668.The results reported in this manuscript show, for the first time, that Aβ(42) can impact upon the AβPP phosphorylation state at the Thr668 residue. This novel finding supports a putative model, whereby Aβ can modulate the phosphorylation state of AβPP regulating its processing and consequently its own production. Furthermore, the data presented shows that in primary cortical neurons, GSK3β and Cdk5 are involved in AβPP phosphorylation at this residue and that PP1 and PP2B participate in AβPP dephosphorylation. Consistent with other reports, Aβ was reports, capable of increasing tau phosphorylation at the Ser396 and Ser262 residues. This peptide is therefore a strong candidate for promoting the cross talk between signaling pathways, which simultaneously result in AβPP and tau hyperphosphorylation. In closing, the Aβ effect on protein kinases and protein phosphatases may constitute an alternative mechanism by which the peptide is able to modulate the phosphorylation state of both AβPP and tau in AD.