New research suggests a connection between disrupted energy production and the development of late-onset Alzheimer’s disease (LOAD).
Investigators from McLean Hospital and Harvard Medical School believe their findings support the hypothesis that impairment in multiple interacting components of bioenergetics metabolism could be the root cause of Alzheimer’s disease (AD).
The research team, led by Kai C. Sonntag, M.D., Ph.D., and Bruce M. Cohen, M.D., Ph.D., contend the metabolic connection has several implications for understanding and developing potential therapeutic intervention in LOAD.
“Our results support the hypothesis that impairment in multiple interacting components of bioenergetics metabolism may be a key mechanism underlying and contributing to the risk and pathophysiology of this devastating illness,” Sonntag said. Sonntag is an associate stem cell researcher at McLean Hospital and an assistant professor of psychiatry at Harvard Medical School.
For three decades, it has been thought that the accumulation of small toxic molecules in the brain, called amyloid beta, or in short, Aβ, is central to the development of Alzheimer’s disease (AD).
Strong evidence came from studying familial or early-onset forms of AD (EOAD) that affect about five percent of AD patients and have associations with mutations leading to abnormally high levels or abnormal processing of Aβ in the brain.
However, the “Aβ hypothesis” has been insufficient to explain the pathological changes in the more common LOAD, which affects more than five million seniors in the United States.
“Because late-onset Alzheimer’s is a disease of age, many physiologic changes with age may contribute to risk for the disease, including changes in bioenergetics and metabolism,” said Cohen, director of the Program for Neuropsychiatric Research at McLean Hospital and the Robertson-Steele Professor of Psychiatry at Harvard Medical School.
“Bioenergetics is the production, usage, and exchange of energy within and between cells or organs, and the environment. It has long been known that bioenergetic changes occur with aging and affect the whole body, but more so the brain, with its high need for energy.”
According to Sonntag and Cohen, it has been less clear what changes in bioenergetics are underlying and which are a consequence of aging and illness.
In their study, Sonntag and Cohen analyzed the bioenergetic profiles from LOAD patients and healthy controls, as a function of age and disease.
The scientists discovered the LOAD patients had a deficiency in the area of a cell called the mitochondria, a critical cell component responsible for generating energy within the cell. Because of this deficit, the cells must turn to other sources of energy, such as glycolytic activity, to maintain energy supply.
“This response is indicative of failing mitochondria and fits with current knowledge that aging cells increasingly suffer from oxidative stress that impairs their mitochondrial energy production,” said Sonntag.
Cohen added that because the brain’s nerve cells rely almost entirely on mitochondria-derived energy, failure of mitochondrial function, while seen throughout the body, might be particularly detrimental in the brain.
The study’s results link to findings from other studies that decreasing energy-related molecules are features of normal aging. The suggestion is that abnormalities in processes involving these molecules may also be a factor in neurodegenerative diseases like LOAD.
Whether modulating these compounds could slow the aging process and prevent or delay the onset of LOAD is unknown. However, several clinical trials are currently under way to test this possibility. Other changes are unique to AD, and these, too, may be targets for intervention.
While these findings are significant, the paper’s authors emphasize that the pathogenesis of LOAD is multifactorial, with bioenergetics being one part of risk determination and note that the skin fibroblasts studied are not the primary cell type that is affected in LOAD.
“However, because bioenergetics changes are body-wide, observations made in fibroblasts may also be relevant to brain cells,” said Sonntag.
“In fact, metabolic changes like diminished glucose uptake and insulin/IGF-1 resistance may underlie the association between various disorders of aging, such as type II diabetes and AD.”
Sonntag and Cohen are already in the midst of follow-up work aiming to study these bioenergetics features in brain nerve cells. It is the group’s hope that findings from these studies will reveal further insight into the role of bioenergetics in LOAD pathogenesis and provide novel targets for intervention — both prevention and treatment.
Source: McLean Hospital