Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models