The mechanistic disconnect between Rett syndrome pathogenesis (MECP2 mutations causing transcriptional dysregulation) and Alzheimer’s disease mechanisms (amyloid cascade, tauopathy, neuroinflammation) underscores that neuroprotective efficacy in one neurological disorder does not predict therapeutic benefit for a distinct pathophysiology, necessitating AD-specific mechanistic validation. Here, MECP2 is linked to atypical Rett syndrome.