PROTAC-mediated multi-target protein degradation in Alzheimer's disease: mechanistic insights, therapeutic applications, and translational challenges.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple interacting pathological mechanisms. Among these, the core driving factor is the accumulation of abnormally folded, neurotoxic proteins. Current therapeutic options, particularly immunotherapies, remain limited due to their reliance on immune-mediated clearance, the need for high-dose administration, and their inability to access intracellular targets, making them less patient-friendly and therapeutically efficient. This is precisely where proteolysis-targeting chimera (PROTAC) technology offers a transformative advantage. By harnessing the ubiquitin-proteasome system (UPS), PROTACs can selectively recruit degradation machinery to target proteins, thereby facilitating their ubiquitination and subsequent clearance. This mechanism allows PROTACs to efficiently eliminate pathogenic proteins while overcoming several inherent limitations of both traditional occupancy-based inhibitors and antibody-based therapies. In this review, we compare currently available AD therapies to highlight the advantages and mechanistic rationale underlying the promise of PROTAC technology in this field. We further discuss the molecular principles of PROTAC-mediated protein degradation and its emerging applications in tackling protein aggregation pathologies, focusing on both established and novel therapeutic targets. By drawing insights from existing PROTAC studies, we aim to inform future design strategies that reduce off-target effects, accelerate candidate optimization, and ultimately contribute to the development of a new generation of AD therapeutics.