Dysfunctional muscle mitochondria linked to higher dementia risk

Lower mitochondrial function in skeletal muscle increases the risk of mild cognitive impairment (MCI) or dementia in older adults, according to an NIA study.The results, published in Alzheimer's & Dementia, also indicate a link between lower mitochondrial function and brain changes associated with Alzheimer's disease. The findings suggest that age-related mitochondrial dysfunction may contribute to the development of Alzheimer's.

Mitochondria are cellular powerhouses, producing most of the energy cells use to function. With aging, mitochondrial function declines. Previous studies in mice have shown a connection between mitochondrial dysfunction and higher amounts of brain amyloid plaques, a hallmark of Alzheimer's. In this study, NIA scientists examined whether mitochondrial dysfunction in muscle is linked to future risk of MCI or dementia. They also investigated the association between mitochondrial function and pathological brain changes associated with Alzheimer's.

The researchers analyzed data collected over several years from participants enrolled in the Baltimore Longitudinal Study of Aging (BLSA). This data includes measures of cognitive function, as well as markers of Alzheimer's in blood samples and PET brain scans. Notably, the BLSA study also measures mitochondrial function in thigh muscle using an MRI body scan taken before, during, and after exercise. The researchers identified 469 participants with normal cognition at the time of mitochondrial function testing. After this initial assessment, they analyzed changes in cognition and blood and brain biomarkers for Alzheimer's.

Based on cognition test results collected over approximately five years, the researchers found lower mitochondrial function in muscle was associated with an increased risk of developing MCI or dementia. In comparison, participants with higher muscle mitochondrial function were less likely to develop cognitive impairment. These associations remained even after scientists adjusted for the participants' fitness level and genetic risk for Alzheimer's.

When the researchers analyzed PET scans and blood samples for proteins associated with Alzheimer's, they found higher muscle mitochondrial function was related to lower levels of brain amyloid deposits and blood proteins associated with neuroinflammation. The amount of tau tangles in the brain, however, was not significantly associated with muscle mitochondrial function.

Overall, the study's findings suggest mitochondrial dysfunction in muscle is related to future risk of MCI or dementia and the development of biomarkers for Alzheimer's. Future studies will focus on the cellular pathways involved, as well as examine whether mitochondrial function in muscle reflects mitochondrial function in the brain. As scientists continue to explore the connections between lifestyle and dementia risk, these results indicate that strategies to improve mitochondrial function in muscle may be beneficial for brain health.

This research was supported by the NIA Intramural Research Program.

These activities relate to NIH's AD+ADRD Research Implementation Milestone 2.B, "Establish new research programs that employ data-driven, systems-based approaches to understand the interaction between peripheral systems (in particular: immune, metabolic, microbiome) and the brain and the impact of this interaction on brain aging and neurodegeneration."

Reference:

Tian Q, et al. Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer's disease and neurodegeneration. Alzheimer's & Dementia. 2023;19(10):4436-4445. doi:10.1002/alz.13388.