The Braak Paradox: When Parkinson’s pathology and clinical progression disconnect. For more than two decades, the Braak hypothesis has shaped how we think about Parkinson’s disease, suggesting that abnormal alpha-synuclein pathology spreads through the brain in a predictable sequence as the disease advances. What resonates with me about this new study by di Biase and colleagues, and the accompanying thoughtful editorial by Rodríguez-Violante in Neurology, is that the biology may be far more complicated than the model. In 61 people with autopsy-confirmed Parkinson’s disease, Braak stage did not correlate with motor disability, disease duration, age at death, or brain weight. In other words, having more widespread alpha-synuclein pathology did not necessarily mean having more advanced clinical disease. The editorial importantly reminds us that this finding does not invalidate Braak staging or the importance of alpha-synuclein, but rather exposes the limitations of using pathology as a clock for clinical progression. Parkinson’s is not one disease following one predictable path, and the frequent presence of other pathologies, including tau, amyloid, and vascular disease, further complicates the picture. For me, the lesson is that we must be careful not to confuse what we see under the microscope with what patients actually experience. As we develop biological staging systems, biomarkers, and disease-modifying therapies, we need to measure not only abnormal proteins but also neuronal loss, clinical disability, and the individual trajectories of people living with Parkinson’s. The patient, not the pathology, must remain at the center of our science. neurology.org/doi/10.1212/WN…