Alzheimer's researchers link glucose metabolism to disease pathology, uncovering new drug targets

Much of the Alzheimer’s disease research over the past several years has focused on the proteins amyloid and tau, which are known to clump up in the brain and are thought to be the cause of memory loss and other telltale symptoms. But a new study, born from a collaborative effort among research centers across the country, suggests that other proteins may play a role in Alzheimer’s—and they could offer new druggable targets.

The team, led by the Emory School of Medicine, discovered that the cognitive impairment associated with Alzheimer’s is associated with proteins that regulate glucose metabolism. Proteins that protect support cells in the brain called astrocytes and microglia also play a key role in Alzheimer’s pathology. They reported the findings in the journal Nature Medicine.

The researchers made the discovery by studying brain tissue from 2,000 Alzheimer’s patients and 400 cerebral spinal fluid samples that were collected by the Emory Goizueta Alzheimer's Disease Research Center and several other research institutions. They analyzed the expression patterns of more than 3,000 proteins.

Previous research from Emory and the National Institutes of Health's National Institute on Aging (NIA) found that abnormalities in the process by which the brain breaks down glucose were associated with amyloid plaques in the brain and the onset of memory loss. This study built on that finding by showing the proteins that govern how cells derive energy from glucose are elevated in the cerebral spinal fluid of patients with Alzheimer’s. There was also an uptick of those proteins in people whose brains show signs of the disease but who are not yet showing symptoms.

"We've been studying the possible links between abnormalities in the way the brain metabolizes glucose and Alzheimer's-related changes for a while now," said co-author Madhav Thambisetty, M.D., Ph.D., an investigator at the NIA, in a statement. "The latest analysis suggests that these proteins may also have potential as fluid biomarkers to detect the presence of early disease."

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Thambisetty and colleagues observed that changes in the proteins that govern glucose metabolism prompted an anti-inflammatory reaction from glial cells. They concluded that Alzheimer’s kicks off processes in the brain that are designed to protect nerve cells. The discovery of glucose-related proteins in cerebral spinal fluid boosts that hypothesis, they said in the study.

The NIA has backed several research efforts focused on searching for Alzheimer’s treatments that capitalize on the role of glucose metabolism. The NIA funded early studies of the drug T3D-959 from North Carolina-based T3D Therapeutics, which is targeting aberrant glucose and fat metabolism in the brain. Last November, T3D raised $15 million in a series B funding round to advance the drug into clinical trials.

Other research groups are searching for ways to prevent the buildup of amyloid in the brain. They include a team at Rensselaer Polytechnic Institute, which published research in February on a compound that blocks the precursor enzyme gamma secretase from making amyloid.

The Emory-led team has made its latest research on glucose metabolism and Alzheimer’s available to the research community on the AD Knowledge Portal. The data “can be used as a rich source of new targets for the treatment and prevention of Alzheimer's,” said Suzana Petanceska, Ph.D., a program director at NIA who oversees its Alzheimer’s target discovery program.