Trofinetide’s FDA approval for Rett syndrome provides established CNS penetration precedent and favorable safety profiles, but the complete absence of Alzheimer’s-disease-specific preclinical or clinical data requires systematic validation in APP/PS1, 3xTg-AD, or 5xFAD transgenic mice, evaluating effects on amyloid pathology, tau phosphorylation, synaptic dysfunction, and cognitive outcomes before clinical translation consideration. Here, APP is linked to atypical Rett syndrome.