Amyloid removal may reduce tau buildup and neurodegeneration in Alzheimer’s disease
In a brain autopsy of a clinical trial participant, regions cleared of amyloid showed little tau buildup, while nearby areas with persistent amyloid had greater signs of damage.
An analysis of the brain of a deceased Alzheimer’s disease (AD) clinical trial participant found that regions where an anti-amyloid therapy successfully cleared amyloid plaques showed little to no evidence of tau tangles, a hallmark of AD closely linked to neurodegeneration and cognitive decline. In contrast, neighboring areas where amyloid remained showed substantially more tau pathology and signs of ongoing brain damage.
The findings provide rare human evidence that clearing amyloid plaques may have long-term effects on the biological processes that drive AD. The study also suggests that removing amyloid early and extensively may slow the progression of the disease by limiting the accumulation of tau and subsequent neurodegeneration, according to findings presented today at the 2026 Alzheimer’s Association International Conference by researchers from the Perelman School of Medicine at the University of Pennsylvania. The report was also published in JAMA.
“Seeing both disease patterns side-by-side in the same brain gave us a rare opportunity to understand how amyloid removal affects other proteins that contribute to Alzheimer’s disease,” said co-senior author David Wolk, MD, co-director of the Penn Memory Center, and director of the Penn Alzheimer’s Disease Research Center. “The findings provide some of the clearest human evidence to date that anti-amyloid therapies may limit the accumulation of tau and slow the brain changes that lead to memory loss and cognitive decline.”
New therapies, longstanding questions
Two proteins are central to AD: beta-amyloid forms plaques that accumulate outside brain cells, while tau forms tangles inside neurons. Together, these proteins are believed to contribute to the nerve cell damage that ultimately causes symptoms such as memory loss, personality changes, and impaired thinking.
Drugs that clear amyloid plaque have transformed treatment landscape in recent years. Aducanumab was the first therapy in this class to receive accelerated FDA-approval, but is no longer marketed as newer, more effective treatments, donanemab (Kisunla) and lecanemab (Leqembi), that work through a similar mechanism received full FDA-approval.
Scientists have long suspected that amyloid accumulation enables tau tangles to take hold. However, opportunities to directly examine how amyloid removal affects tau are rare because relatively few patients who have received anti-amyloid therapies have come to autopsy.
Rare opportunity to look at the brain of a trial participant
This report analyzed the brain of a man in his fifties, diagnosed with mild cognitive impairment due to AD, who enrolled in a clinical trial of aducanumab and received 30 doses over four and a half years. He died approximately four years after his final treatment and more than a decade after symptoms first began. One of his final wishes was to donate his brain for research at the Center for Neurodegenerative Disease Research within the Department of Pathology and Laboratory Medicine.
When neuropathologists examined the brain, they found an unusual patchwork pattern.
Areas called gyri, the crests of the brain’s folds, were largely cleared of amyloid plaques and showed minimal tau accumulation. Nearby sulci, the grooves between those folds, retained substantial amyloid and displayed much greater tau accumulation, inflammation, and neurodegeneration. The pattern closely matched brain imaging collected during the participant’s life, which had shown uneven amyloid clearance across different regions of the brain.
“Many previous reports have shown either extensive amyloid clearance or limited clearance,” said co-senior author Edward B. Lee, MD, PhD, the John Q. Trojanowski, MD, PhD Professor for Neurodegenerative Disease Research in Pathology and Laboratory Medicine. “This case represented a unique ‘Goldilocks’ scenario in which some regions cleared amyloid and others did not. It allowed us to directly compare what happened next in neighboring brain regions and better understand the relationship between amyloid, tau, and neurodegeneration.”
Implications for current and future therapies
The findings are particularly relevant because newer, more effective FDA-approved AD therapies work through a similar amyloid-removal mechanism.
While this study describes a single patient and cannot determine exactly how much amyloid removal is needed to produce long-term benefits, the results suggest that extensive plaque clearance may have lasting effects on the downstream processes that drive AD. They also raise the possibility that some treatment benefits may emerge over longer timeframes than the 18-month periods typically evaluated in clinical trials.
Future research will investigate why some brain regions appear better able to clear amyloid than others and whether enhancing those clearance pathways could improve treatment outcomes. Researchers are also studying whether treatment earlier in the disease process—before substantial tau accumulation occurs—can delay or prevent AD altogether.
“Patients may accumulate amyloid for years before symptoms appear,” said first author Christopher A. Brown, MD, PhD, an assistant professor of Neurology. “This case suggests that removing amyloid early may help limit the changes that ultimately damage brain cells. Ongoing trials will help determine whether starting treatment before symptoms begin can provide even greater benefit.”
For more information on Alzheimer’s disease clinical trials at Penn Medicine, visit the Penn Memory Center’s Resource for Research.
This research was supported by the National Institutes of Health (P30-AG072979, RF1-AG069474, R01-AG056014, R01-AG055005, R01-AG072796, R01-AG065341, P01-AG084497).Media contact
Kelsey Geesler
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Kelsey.Geesler@pennmedicine.upenn.edu
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