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. This evidence concerns the gene MECP2 and tauopathy.