Molecular Glue Degraders Enhance CAPRIN1‐Dependent Lysosomal Degradation of APP and Reduce Amyloid β in Alzheimer's Disease

The amyloid cascade involving the production and deposition of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP) is a leading hypothesis in the pathogenesis of Alzheimer's disease (AD). However, disease‐modifying therapies targeting this cascade remain an unmet challenge. Here, we identify small molecules that degrade APP and reduce Aβ production through a targeted protein degradation strategy. Using genetically engineered APP cell models and induced pluripotent stem cell (iPSC)‐derived neurons from patients with AD, we demonstrate that cytoplasmic activation/proliferation‐associated protein 1 (CAPRIN1) is expressed in neurons and physically interacts with APP. Screening of a CAPRIN1‐targeted compound library identified compound 0043, which promotes intracellular APP degradation and reduces extracellular Aβ release. Structure–activity relationship optimization of 0043 derivatives yielded compound 0152 with improved potency and blood–brain barrier permeability. In AD iPSC‐derived neurons, these compounds enhance CAPRIN1–APP interactions and promote CAPRIN1‐dependent APP degradation through the endolysosomal pathway. CAPRIN1 is predominantly expressed in neurons in AD postmortem brains and iPSC‐derived brain organoids. Systemic administration of compound 0152 significantly reduced APP levels, Aβ production, and amyloid burden in 5xFAD mice. These findings establish CAPRIN1‐dependent, lysosome‐targeted molecular glue degraders as a potential APP‐targeted therapeutic strategy for AD.