Validating the Amyloid Cascade Through the Revised Criteria of Alzheimer's Association Workgroup 2024 for Alzheimer Disease

BACKGROUND AND OBJECTIVES: The amyloid cascade hypothesis posits that Alzheimer disease (AD) progresses from amyloid deposition to tau deposition, neurodegeneration, and eventually cognitive impairment and is the foundation of the revised criteria of Alzheimer's Association Workgroup 2024 (AA-2024). To account for copathologies and cognitive resilience that affect the penetrance of the AD cascade, AA-2024 introduced a 2-dimensional biological-clinical staging framework. We aimed to estimate the proportion of persons along the AD continuum whose biological and clinical trajectories align with the amyloid cascade. METHODS: test, and differences among the 5 methods were tested using the Cochran Q test. DISCUSSION: Only approximately one-third of persons with an AA-2024 diagnosis of AD complied with the predictions of the amyloid cascade hypothesis. These results suggest the heterogeneity in how clinical symptoms and pathology are coupled along the AD continuum, which has significant implications for interpreting completed antiamyloid clinical trials and designing future studies.