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Scientists have identified a previously unrecognized feature of Alzheimer’s disease in the form of clustered, damaged cellular power plants within nerve fibers. These structures, dubbed “mitochondrial plaques,” appear to arise from a breakdown in the brain’s cellular waste disposal system. The findings, published in Nature Neuroscience, suggest that targeting these newly discovered plaques alongside traditional therapies might offer a more comprehensive approach to slowing cognitive decline.
Alzheimer’s disease is a progressive brain condition that causes memory loss and cognitive impairment. For years, therapies have largely targeted amyloid plaques, which are abnormal clumps of protein that accumulate outside brain cells. But these treatments only offer limited benefits, leading researchers to explore other cellular changes occurring in the disease.
One area of interest involves mitochondria, the tiny structures inside cells that generate energy. When mitochondria become damaged, cells rely on a recycling process called mitophagy to clear them out. During mitophagy, damaged mitochondria are delivered to lysosomes, which are acidic compartments that act as the cell’s waste disposal system.
If lysosomes fail to function correctly, cellular garbage can pile up. A 2026 preprint study indicated that these cellular waste-disposal compartments begin failing early in Alzheimer’s disease, even before classic amyloid plaques form. This early failure helps explain why damaged mitochondria might accumulate rather than being properly degraded.
In this new study, researchers set out to map exactly how and where this mitochondrial recycling goes wrong. “One of our earlier studies suggested that mitophagy, the process by which cells remove damaged mitochondria, may be impaired in Alzheimer’s disease (AD) brains,” Xiuli Dan, a research assistant professor in Paul Robbins’ lab at the University of Minnesota, told PsyPost.
“However, the evidence at that time was largely indirect,” Dan explained. “We were looking at changes in proteins involved in mitophagy and the accumulation of damaged mitochondria, but we did not yet have a way to directly measure mitophagy or determine which regions of the brain were most affected.”
The project to directly visualize mitochondrial degradation in specific brain regions spanned multiple research institutions. “This work was initiated in Dr. Bohr’s lab at NIH and completed at Dr. Robbins’ lab at UMN after I moved here,” Dan noted.
To explore these questions, the scientists used genetically modified mice designed to develop Alzheimer’s-like symptoms. These mice were also engineered to express a fluorescent tag in their mitochondria that glows green in neutral environments but shifts to red when placed in acidic lysosomes. This color-coding allowed the researchers to track exactly which mitochondria were being actively digested and which were simply floating in the cell.
“Using this model, we made an unexpected observation that acidic mitochondria accumulated prominently and specifically in AD mouse brains,” Dan said. “This unexpected finding motivated us to investigate these accumulations further, which ultimately led to our identification and characterization of mitochondrial plaques.”
The team examined brain slices from these mice at various ages using high-resolution microscopes. They also studied a second mouse model of Alzheimer’s disease and examined postmortem brain tissue from human Alzheimer’s patients to verify their findings.
The researchers observed large, abnormal accumulations of mitochondria in the cortex and hippocampus, regions of the brain important for memory. They named these massive clusters “mitochondrial plaques.” These structures were multilayered and much larger than typical mitochondrial recycling spots seen in healthy cells.
These mitochondrial plaques were found specifically within swollen, damaged sections of nerve fibers. Approximately 60 percent of the material inside a typical mitochondrial plaque was acidic, meaning it had been swallowed by lysosomes. The remaining portion consisted of mitochondria sitting in a neutral environment, waiting to be degraded.
Tracking the mice over time showed that mitochondrial plaques appear as early as 15 weeks of age, roughly the same time amyloid plaques begin to form. Initially, the brain tries to compensate by sending more lysosomes to break down the mitochondrial buildup. But the lysosomes in the Alzheimer’s models lacked the necessary acidity and enzymes to digest the waste, causing the mitochondria to pile up.
Over time, these mitochondrial clusters often grew into and merged with amyloid plaques, creating what the researchers described as mixed plaques. Around 60 percent of the local amyloid precursor protein was found trapped inside these mitochondrial clusters. However, the study indicates that mitochondrial plaques can also exist completely independently of amyloid plaques, especially in the early stages of the disease.
To confirm that this is not just a phenomenon unique to mice, the team examined postmortem hippocampal tissue from human Alzheimer’s patients and age-matched healthy controls. The human Alzheimer’s brains contained the same large, mitochondria-rich clusters tightly associated with lysosomes. This feature was entirely absent in the healthy brains.
“The major takeaway is that mitochondrial plaques, or MPs, are a previously unrecognized pathological structure in AD, composed largely of mitochondria that become trapped and are not properly degraded inside neurons,” Dan explained.
As with all research, there are some caveats to consider. The study heavily relied on mouse models and a simplified cell-culture system to track the timeline of mitochondrial buildup. These models provide a controlled way to observe brain changes over time, but they do not capture the full complexity of human Alzheimer’s disease.
There are a few things to keep in mind regarding the exact sequence of events. While the images and molecular tests suggest that mitochondrial accumulation happens first, followed by a failed lysosomal response, the study cannot definitively map the entire chain of causality. Other pathological features, such as tau protein tangles or chronic inflammation, might also play overlapping roles in disrupting the brain’s waste disposal systems.
“Importantly, our findings suggest that MP formation is not simply a problem of lysosomal degradation,” Dan said. “The process appears to begin with an abnormal accumulation of mitochondria, followed by impaired lysosomal processing and clearance.”
“We hope this provides a new way to think about mitochondrial pathology in AD and may eventually help identify new biomarkers or therapeutic targets,” she added.
Future research will need to explore whether treatments designed to boost lysosomal acidity and improve mitochondrial recycling can prevent the formation of these plaques. Addressing both amyloid plaques and mitochondrial plaques simultaneously could provide a more effective strategy for preserving brain function.
The study, “Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer’s disease,” was authored by Xiuli Dan, Deborah L. Croteau, Wenlong Liu, Xixia Chu, Ross A. McDevitt, Paul D. Robbins, and Vilhelm A. Bohr.
