Although the exact cause of Alzheimer’s disease remains unknown, it is widely accepted that the accumulation of certain proteins—beta-amyloid and tau—in the brain characterizes the disease. Edward Anderton, PhD, a postdoctoral researcher at The Buck Institute for Research on Aging in California and co-first author of a recent study published in the journal *GeroScience*, explained that neurodegenerative diseases of aging are marked by the buildup of large protein clumps in the brain, termed insoluble protein aggregates. In Alzheimer’s disease, beta-amyloid forms plaques closely linked to neuronal death and brain inflammation.

These plaques, however, contain numerous additional proteins that have been largely overlooked until now. Anderton and researchers at The Buck Institute decided to investigate how the general accumulation of insoluble proteins might accelerate Alzheimer’s disease. Using a worm model, scientists discovered that both natural aging and beta-amyloid drive other proteins to become insoluble. They then used a compound to enhance mitochondrial health in these insoluble proteins, effectively delaying the toxic effects of beta-amyloid.

Mitochondria, often called the powerhouses of the cell, have recently become a focal point in Alzheimer’s research. Scientists are exploring whether “repairing” dysfunctional mitochondria with age might help preserve brain health. Manish Chamoli, PhD, a research scientist at The Buck Institute and co-first author of the study, likens proteins to tiny machines in our cells that need to be a specific shape to function properly. Misfolded proteins can aggregate, forming insoluble protein clumps due to factors like stress, aging, or damage. In Alzheimer’s disease, the brain fails to dispose of these damaged proteins correctly.

Using the microscopic worm *Caenorhabditis elegans*, researchers observed that aging worms accumulate clumps of insoluble proteins, similar to the protein aggregates found in the brains of Alzheimer’s patients. The study aimed to understand the connection between protein clumps in normal aging and Alzheimer’s disease. It revealed that beta-amyloid causes significant insolubility in other proteins, particularly those in the core insoluble proteome, which includes proteins linked to other neurodegenerative diseases like Parkinson’s and Huntington’s.

Researchers hypothesized that boosting the quality of mitochondrial proteins could counteract beta-amyloid’s negative effects. They found that mitochondrial proteins, particularly those in the electron transport chain, became insoluble under beta-amyloid influence. By enhancing mitochondrial function through mitophagy, a process that recycles damaged mitochondria, they aimed to mitigate beta-amyloid’s toxicity. The compound urolithin A, derived from foods like pomegranates and walnuts, was used to clear insoluble proteins from mitochondria, showing promising results.

Verna R. Porter, MD, a neurologist and director at the Pacific Neuroscience Institute, noted that these findings suggest beta-amyloid contributes to widespread protein insolubility, especially affecting mitochondrial proteins. This mirrors changes seen in aging and indicates a potential novel approach to addressing Alzheimer’s disease by targeting mitochondrial health. Porter suggested that future clinical trials could test the efficacy of mitochondrial health-boosting compounds, including urolithin A, in Alzheimer’s patients. Further exploration of the mechanisms by which beta-amyloid disrupts mitochondrial function could reveal additional therapeutic targets.