Scientists discover previously unknown “mitochondrial plaques” in Alzheimer’s disease brains

Scientists have discovered a previously unknown feature in Alzheimer's disease brains known as "mitochondrial plaques." These structures consist of damaged cellular power plants, or mitochondria, that accumulate in nerve fibers due to a breakdown in the brain's cellular waste disposal system. The findings, published in Nature Neuroscience, suggest that targeting these plaques alongside current treatments may help slow cognitive decline.

Alzheimer's disease is a progressive brain condition causing memory loss and cognitive impairment. Currently, therapies mainly target amyloid plaques, abnormal protein clumps outside brain cells, but these treatments have limited benefits, prompting researchers to investigate other cellular changes in the disease. Mitochondria, the energy-generating structures inside cells, can become damaged.

When this happens, cells use a recycling process called mitophagy to remove them. Mitophagy delivers damaged mitochondria to lysosomes, acidic compartments that act as the cell's waste disposal system. If lysosomes function improperly, cellular waste accumulates. A 2026 preprint study revealed that lysosome function begins failing early in Alzheimer's disease, even before amyloid plaques form, explaining why damaged mitochondria might accumulate.

Researchers aimed to determine how and where this mitochondrial recycling goes wrong. Using genetically modified mice with Alzheimer's-like symptoms and fluorescent tags in their mitochondria, they discovered large, abnormal accumulations of mitochondria in the cortex and hippocampus, brain regions crucial for memory. Named "mitochondrial plaques," these clusters were multilayered and located in swollen, damaged nerve fiber sections.

Around 60% of a typical mitochondrial plaque was acidic, meaning it had been digested by lysosomes, while the rest consisted of mitochondria waiting to be degraded. The study found that mitochondrial plaques emerged as early as 15 weeks of age, the same time amyloid plaques begin forming. Initially, the brain attempts to compensate by sending more lysosomes to break down the buildup, but the lysosomes in Alzheimer's models lack the necessary acidity and enzymes to digest the waste, causing mitochondria to pile up.

In some cases, these clusters merged with amyloid plaques, forming mixed plaques. Approximately 60% of local amyloid precursor protein was found trapped inside these mitochondrial clusters. However, mitochondrial plaques can also exist independently of amyloid plaques, particularly in early disease stages. Postmortem human Alzheimer's brains showed the same large, mitochondria-rich clusters associated with lysosomes, absent in healthy brains.

The researchers concluded that mitochondrial plaques are a previously unrecognized pathological structure in Alzheimer's disease, composed mainly of trapped and undegraded mitochondria within neurons. Limitations include reliance on mouse models and simplified cell-culture systems to observe brain changes over time, which may not fully capture human Alzheimer's complexity.