Higher Brain Glucose Levels Indicate Severe Alzheimer's

Greater reductions in brain glycolysis demonstrated a relationship to symptoms of Alzheimer’s disease like memory problems.

Madhav Thambisetty, MD, PhD

According to a recent study published The Journal of the Alzheimer’s Association, scientists have found a connection between abnormalities in how the brain breaks down glucose and the onset of eventual outward symptoms of Alzheimer’s disease.

The study, supported by the National Institute of Aging (NIA), part of the National Institutes of Health, found a connection between abnormalities in the brain breaking down glucose and the severity of the signature amyloid plaques and the tangles in the brain, and as well as the onset of eventual outward symptoms of Alzheimer’s disease.

“While these results clearly show that abnormalities in brain glucose metabolism are linked to Alzheimer's disease pathogenesis, they suggest a more complex relationship between levels of blood glucose and Alzheimer’s symptoms in early stages of the disease,” Madhav Thambisetty, MD, PhD, investigator and chief, Unit of Clinical and Translational Neuroscience, NIA’s Laboratory of Behavioral Neuroscience, told MD Magazine. “Understanding this relationship in future studies is important in establishing optimal blood glucose levels to reduce Alzheimer’s risk in older individuals.”

Researchers, led by Thambisetty, measured glucose levels in various brain regions, some vulnerable to Alzheimer’s disease pathology like the frontal and temporal cortex, and some areas that are resistant like cerebellum. Brain tissue samples at autopsy were examined from participants in the Baltimore Longitudinal Study of Aging (BLSA).

Three groups of BLSA participants were analyzed, healthy controls; those with Alzheimer’s symptoms during life and with confirmed Alzheimer’s disease pathology in the brain at death; and individuals without symptoms during life but with significant levels of Alzheimer’s pathology found in the brain post-mortem.

Distinct abnormalities in glycolysis were found with evidence linking the severity of the abnormalities to the severity of Alzheimer’s pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles found in the brains of people with Alzheimer’s.

Greater severe reductions in brain glycolysis were also related to the expression of symptoms of Alzheimer’s disease like memory problems.

While it’s known that diabetes and Alzheimer’s share commonalities, they are often difficult to evaluate since insulin isn’t needed for glucose to enter the brain or to get into neurons.

The brain’s usage of glucose was tracked by measuring ratios of the amino acids serine, glycine and alanine to glucose, allowing them to assess rates of the key steps of glycolysis.

Researchers found that activities of enzymes controlling these key glycolysis steps were lower in Alzheimer’s cases compared to normal brain tissue samples and lower enzyme activity was associated with more severe Alzheimer’s pathology in the brain and development of symptoms.

Researchers used proteomics, the large-scale measurement of cellular proteins, to tally levels of GLUT3, a glucose transporter protein, in neurons. Findings demonstrated that

GLUT3 levels were lower in brains with Alzheimer’s pathology compared to normal brains, and the levels were also connected to the severity of tangles and plaques.

Blood glucose levels were checked in study participants years before they passed, finding that greater increases in blood glucose levels correlated with greater brain glucose levels at death.

“For some time, researchers have thought about the possible links between how the brain processes glucose and Alzheimer’s,” Richard Hodes, MD, director, NIA, said in a statement. “Research such as this involves new thinking about how to investigate these connections in the intensifying search for better and more effective ways to treat or prevent Alzheimer’s disease.”

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