Elevated metabolism as an Alzheimer’s indicator

Early mitochondrial hypermetabolism in Alzheimer's mice.

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Researchers at the Karolinska Institutet found that in the early stages of Alzheimer’s, the hippocampus, a part of the brain, becomes more active metabolically. This discovery suggests new ways to intervene early in the disease. Alzheimer’s is the most common type of dementia and affects around 20,000 people in Sweden each year. The researchers have revealed that increased metabolic activity in the cell’s powerhouses, called mitochondria, is an early sign of the disease.

The study used mice that develop Alzheimer’s like humans. Young mice first showed increased metabolism, then had synaptic changes due to problems in the cell’s recycling system (autophagy). This discovery won a Nobel Prize in 2016. Over time, metabolism in the Alzheimer’s brain usually decreases, leading to the breakdown of synapses. The same decline was observed in older mice with the disease for a longer time.

Per Nilsson, a researcher at the Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet said, “The disease starts to develop 20 years before the onset of symptoms, so it’s essential to detect it early – especially given the retardant medicines that are beginning to arrive. Metabolic changes can be a diagnostic factor in this.”

Maria Ankarcrona, a researcher from the same department, mentioned, “It’s interesting that metabolic changes occur before the typical brain plaques form. These energy-related shifts match what we’ve observed in Alzheimer’s brain images. However, now we’ve identified them at an earlier stage.” The study closely involved

  • both researchers’ teams,
  • focusing on the hippocampus in the mouse brain,
  • A region crucial for short-term memory and early affected in Alzheimer’s.

By using RNA sequencing to analyze active genes in the hippocampus cells at different Alzheimer’s stages, researchers found that early in the disease, there’s an increase in mitochondrial metabolism. They also studied synapse changes through electron microscopy and discovered accumulations of autophagosomes disrupting protein function. 

The researchers plan to explore the roles of mitochondria and autophagy in Alzheimer’s further using more accurate mouse models. Dr. Nilsson emphasizes the importance of maintaining functional mitochondria and normal protein metabolism and hopes to test new molecules to slow down the disease. This study received funding from various sources, and the researchers have no conflicts of interest.

In conclusion, high metabolism within the hippocampus emerges as an early and potentially predictive sign of Alzheimer’s disease, even preceding the formation of characteristic brain plaques. This discovery highlights the importance of further investigating the roles of mitochondria and autophagy in Alzheimer’s development, with the potential for new treatments to stabilize these functions to slow the disease’s progression.

Journal reference:

  1. Naia, L., Shimozawa, M., Bereczki, E. et al. Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models. Molecular Psychiatry. DOI: 10.1038/s41380-023-02289-4.
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