An unprecedented analysis conducted on a human brain after death suggested that aducanumab, an experimental drug intended for the treatment of Alzheimer's disease, failed to exert its function homogeneously across all brain areas.
Study and Methodology
The research, published last Sunday (12) in the journal JAMA, was based on the post-mortem examination of an individual who received the treatment for a period of 4.5 years. Scientists from the University of Pennsylvania, located in the United States, conducted the study by comparing brain images and analyses before and after therapy, using the case of a patient with mild cognitive impairment who participated in a clinical trial.
Findings on Drug Action
The findings revealed that certain brain regions showed a decrease in beta-amyloid plaques and a reduction in tau protein accumulation, while other areas maintained signs associated with the progression of Alzheimer's disease. This finding helps explain the inconsistency of results observed in patients treated with drugs targeting these structures.
The studied case was notable for allowing the observation, within the same brain, of areas that responded to the drug and others that did not show the same effect. This disparity provided researchers with an unusual opportunity to evaluate how the elimination of beta-amyloid protein correlates with other modifications related to the pathology. The patient received 30 doses of aducanumab over four and a half years. After his death, four years after the last application, his family authorized the donation of the brain for scientific purposes, which was then compared with brains of people with dementia who did not receive the medication.
Observed Brain Patterns
The evaluation performed after death demonstrated that the outermost layers of the brain had fewer beta-amyloid plaques, while more internal regions of the cortex still contained a significant amount of this material. For the researchers, this pattern indicates that the drug may not have reached all necessary locations to generate a comprehensive effect. According to the responsible scientists, the areas with lower concentrations of beta-amyloid also exhibited fewer tau tangles and less brain tissue loss, strengthening the idea that plaque removal can influence the advancement of other neuronal degenerative processes.
Expert Statements
Edward Lee, a neuropathologist at the University of Pennsylvania and one of the researchers, commented that the case represented a rare situation where some regions eliminated amyloid and others did not, allowing for a direct comparison of what occurred in adjacent areas and improving the understanding of the link between amyloid, tau, and neurodegeneration. David Wolk, a neurologist and director of the University of Pennsylvania's Alzheimer's Disease Research Center, stated that the simultaneous visualization of these different patterns in the same brain provided crucial evidence about the impact of anti-beta-amyloid therapies. Wolk declared that the findings offer some of the clearest human evidence to date that anti-amyloid therapies can restrict tau accumulation and delay brain changes that lead to memory loss and cognitive decline.
Limitations and Treatment Context
Despite the positive signs in this specific case, the researchers themselves warn that it is only one patient. They emphasize that Alzheimer's shows great variation among individuals, and a single autopsy is not sufficient to define the overall efficacy of any therapeutic strategy. Aducanumab had already generated controversy before this analysis; in 2021, the U.S. drug regulatory agency approved the treatment on an accelerated basis, a decision criticized for being based on considered limited results. Later, in 2024, the manufacturer Biogen suspended the production of the drug to focus resources on other Alzheimer's-related initiatives.
The discussion about the role of beta-amyloid plaques remains polarized among experts. While some argue that eliminating this protein in early stages can reduce future damage, others maintain that it may only be a consequence of the disease, not the primary cause of cognitive decline. A review that included 17 clinical trials and over 20,000 participants, cited in the study, indicated that anti-beta-amyloid drugs showed no clinically relevant benefits in people with mild cognitive impairment or mild Alzheimer's dementia.
Future Perspectives
Christopher Brown, a neurologist and lead author of the research, did not rule out the possibility of beta-amyloid remaining a relevant target. The hypothesis raised by the study is that the timing of treatment initiation may be decisive, given that this protein can appear in the brain many years before symptoms appear. Brown assessed that this case suggests that removing amyloid early can help limit changes that harm brain cells. Future studies will need to confirm whether interventions initiated before the onset of symptoms can generate more pronounced effects, while this patient's brain analysis remains important data for understanding why certain treatments affect some brain regions and fail in others.
