Alzheimer's disease (AD) is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), which are composed of the microtubule-binding protein tau. Recent studies suggest a functional link between amyloid and tau pathology, though the mechanisms are unclear. This study shows that tau is cleaved by multiple caspases at a conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-β (Aβ) peptide. Tau cleavage at Asp421 occurs rapidly in Aβ-treated neurons and precedes nuclear apoptosis events. The cleavage product, which lacks the C-terminal 20 amino acids, assembles more rapidly into tau filaments than wild-type tau. A monoclonal antibody (TauC3) specifically recognizes tau truncated at Asp421, and it detects this truncation in AD brain NFTs. These findings suggest a novel mechanism linking amyloid deposition and NFTs in AD: Aβ peptides promote pathological tau filament assembly by triggering caspase cleavage of tau, generating a proteolytic product with enhanced polymerization kinetics. The study also shows that caspase cleavage of tau at Asp421 increases the rate and extent of tau filament assembly in vitro. TauC3 labels the neurofibrillar pathologies of AD, indicating that tau truncated at Asp421 is present in NFTs. These results suggest that caspase-cleaved tau may play a critical role in the pathogenesis of AD by promoting the assembly of pathological tau filaments. The study highlights the importance of caspase activity in AD and provides evidence that tau cleavage at Asp421 is an early event in Aβ-induced neuronal apoptosis. The findings underscore the functional link between amyloid and tau pathology in AD and suggest that caspase-cleaved tau may be a key player in the disease process.Alzheimer's disease (AD) is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), which are composed of the microtubule-binding protein tau. Recent studies suggest a functional link between amyloid and tau pathology, though the mechanisms are unclear. This study shows that tau is cleaved by multiple caspases at a conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-β (Aβ) peptide. Tau cleavage at Asp421 occurs rapidly in Aβ-treated neurons and precedes nuclear apoptosis events. The cleavage product, which lacks the C-terminal 20 amino acids, assembles more rapidly into tau filaments than wild-type tau. A monoclonal antibody (TauC3) specifically recognizes tau truncated at Asp421, and it detects this truncation in AD brain NFTs. These findings suggest a novel mechanism linking amyloid deposition and NFTs in AD: Aβ peptides promote pathological tau filament assembly by triggering caspase cleavage of tau, generating a proteolytic product with enhanced polymerization kinetics. The study also shows that caspase cleavage of tau at Asp421 increases the rate and extent of tau filament assembly in vitro. TauC3 labels the neurofibrillar pathologies of AD, indicating that tau truncated at Asp421 is present in NFTs. These results suggest that caspase-cleaved tau may play a critical role in the pathogenesis of AD by promoting the assembly of pathological tau filaments. The study highlights the importance of caspase activity in AD and provides evidence that tau cleavage at Asp421 is an early event in Aβ-induced neuronal apoptosis. The findings underscore the functional link between amyloid and tau pathology in AD and suggest that caspase-cleaved tau may be a key player in the disease process.