A collaboration between Weill Cornell Medical scientists and other leaders in Alzheimer’s disease research has revealed widespread metabolic changes in the brains of individuals with Alzheimer’s disease. The findings could lead to the development of new treatments aimed at alleviating the metabolic effects of the disease.
For the study, published July 13 in Alzheimer’s Disease and Dementia, researchers compared levels of about 670 metabolites in postmortem human brain tissue samples obtained from people with Alzheimer’s disease and from those without the condition. These metabolites are small molecules that are produced during key metabolic processes in the brain, such as producing energy for brain cells or processing fats necessary for efficient information transmission in the brain.
Levels of more than half of the metabolites were altered in individuals with Alzheimer’s disease. The team linked metabolic changes, memory loss, and a characteristic buildup of protein tangles in the brain. In addition, the investigation revealed a new relationship between cellular osmotic regulation and disease.
“Our study confirms that Alzheimer’s disease causes dramatic metabolic changes in brain tissue,” said Jan Kromsek, assistant professor of computational genomics at Weill Cornell Medicine. “Many changes are associated with the pathology of the disease.”
Kremsik collaborated with Matthias Arnold, associate professor at Duke University and team leader at Helmholtz Zentrum Munich, Germany, Reema Kadura-Daouk, professor at Duke University and a member of the Duke Institute for Brain Science in Durham, North Carolina, and several other scientists to form the Metabolic Disease Consortium for Disease Control and Prevention. Alzheimer’s.
They turned to consortium member Dr. David Bennett, director of the Alzheimer’s Disease Center at Rush University Medical Center in Chicago, for access to brain tissue samples from the Religious Order Study and the Rush Memory and Aging Project. Bennett and his team followed a group of more than 500 elderly volunteers and monitored their brain health for decades. Participants agreed to donate their brains for research after their death.
The study samples provided the team with an unprecedented window into metabolic changes in the brains of people who have experienced cognitive decline. They used high-performance liquid chromatography-mass spectrometry to measure metabolic levels in samples of the brain’s lateral prefrontal cortex, which is responsible for complex tasks such as thinking and planning. They then looked for differences in people who had Alzheimer’s disease, memory loss, or Alzheimer’s-related brain changes compared to individuals who did not have these brain conditions when they died.
“We’ve seen metabolic changes associated with cellular energy, glucose metabolism, inflammation, and fatty acids, all of which have been previously implicated in Alzheimer’s disease,” Krumsik said.
He noted that disruption of glucose, or sugar metabolism, is one of the first changes to be discovered in individuals with Alzheimer’s disease. This observation has led some scientists to suggest that Alzheimer’s disease is “type 3 diabetes” and that poor insulin regulation in the brain deprives brain cells of the energy they need to function. The results of the consortium support this idea.
Krumsik and colleagues found that tau, which accumulates in protein tangles that rupture brain cells, appears to play a more prominent role in disease-related metabolic changes than another disease-related protein called amyloid beta. Both tau and amyloid beta are thought to play essential roles in Alzheimer’s disease, but scientists have fiercely debated whether amyloid beta causes the disease. The study adds further fuel to the debate about the roles of each protein.
The team also discovered impaired regulation, the process that controls the diffusion of water into brain cells, in Alzheimer’s patients. Krumsick explained that osmotic regulation changes the amount of stress on a cell and can interfere with protein folding or other critical functions in cells. This finding is particularly interesting because of the role that amyloid beta and tau proteins play in the disease.
“This is a potential new mechanism in Alzheimer’s disease,” he said.
The team has made its data and analyzes of the study available online to other researchers, and now plans to analyze samples from other brain regions to see if the metabolic effects of the disease differ across the brain. Krumsick is also conducting a National Institutes of Health-funded study using computational strategies to determine whether any drugs currently approved by the U.S. Food and Drug Administration to treat other diseases might improve brain metabolism in Alzheimer’s disease.
Krumsick said the study demonstrates the value of a holistic and unbiased approach to a well-studied disease.
“We simply would not have recognized changes in osmotic regulation if we only looked at a small group of metabolites previously associated with disease,” he said.
Bridget Cohn is a freelance writer at Weill Cornell Medicine.