Researchers from Harvard University have proposed a new model of Alzheimer’s disease that suggests that mitochondria dysfunction may be the precursor to the disease.
The current model of Alzheimer’s is known as the amyloid cascade model, which assumes Alzheimer’s is driven by the accumulation of protein plaques (beta amyloid) in neurons caused by a genetic mutation. While numerous clinical trials have been conducted based on this model, none have shown positive results. That and the fact that genetic mutations only account for about 5% of the disease prompted Lloyd Demetrius, a researcher in population genetics at Harvard’s Museum of Comparative Zoology and Jane Driver, an assistant professor of medicine at Harvard Medical School, to examine this assumption.
“A lot of people are realizing now that we have been focusing on the usual suspects — genetics and proteins ― and that’s brought us to a point where, despite billions of dollars in research, we are no closer to a disease-modifying therapy,” Driver said. “Of course, that’s not to suggest that genetics isn’t important, but I think what we haven’t done is to take the 20,000-foot view and ask if it is even logical to expect that changes to one protein could be responsible for an age-related disease. It just didn’t add up.”
“The late-onset cases, however, are quite different,” Demetrius said. “They increase exponentially with age, and that is one of the most striking characteristics of the disease. As you age, the chances of getting it increase.”
What occurs during the aging process?
As a person ages, the mitochondria in the cells generate less energy. While the mitochondria that produce cellular energy from nutrients such as glucose are quite efficient, this process has the side effect of producing oxygen-free radicals, which can damage mitochondrial DNA and proteins. Demetrius and Driver believe this accumulated damage leads to an energy deficit, triggering a compensatory event they call “metabolic re-programming” — unaffected mitochondria increase output to make up for the energy deficit.
Both the healthy and impaired nerve cells then compete for nutrients, creating a fragile equilibrium. Researchers believe that stress, both physical and emotional, acts as the tipping point that pushes a person in to a disease state like Alzheimer’s. Illnesses such as a stroke or a major depression disrupt the neural system and put additional stress on neurons. Some die, and others have to increase their energy production in order to survive. As a result, impaired neurons use a larger share of the brain’s resources and leave the healthy neurons starving for nutrients.
“When that happens, you have a rapid shift toward Alzheimer’s — what I call pathological aging,” Demetrius said. “The two types of neurons are competing with each other, but the impaired neurons, in view of the particular environment of the aging brain, have a selective advantage.”
Demetrius states that interventions such as exercise, drugs, or nutrient supplementation can help maintain the equilibrium in the neural environment and prevent the brain from shifting in to pathological aging.
“The things we need to do to prevent Alzheimer’s, or at least make a dent in the incidence of the disease, are within our hands,” Driver said.