NEUROLOGY

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Higher Brain Glucose Levels May Mean More Severe Alzheimer’s

 

According to an article published online in Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association (6 November 2017), higher brain glucose levels may mean more severe Alzheimer’s, and thus showing connections between glucose metabolism and Alzheimer’s pathology, symptoms. For the first time, a connection was found between abnormalities in how the brain breaks down glucose and the severity of the signature amyloid plaques and tangles in the brain, as well as the onset of eventual outward symptoms of Alzheimer’s disease. For the study, the authors looked at brain tissue samples at autopsy from participants in theĀ Baltimore Longitudinal Study of Aging (BLSA), one of the world’s longest-running scientific studies of human aging. The BLSA tracks neurological, physical and psychological data on participants over several decades. For the study, the authors measured glucose levels in different brain regions, some vulnerable to Alzheimer’s disease pathology, such as the frontal and temporal cortex, and some that are resistant, like the cerebellum. They analyzed three groups of BLSA participants: those with Alzheimer’s symptoms during life and with confirmed Alzheimer’s disease pathology (beta-amyloid protein plaques and neurofibrillary tangles) in the brain at death; healthy controls; and individuals without symptoms during life but with significant levels of Alzheimer’s pathology found in the brain post-mortem.

 

Results showed distinct abnormalities in glycolysis, the main process by which the brain breaks down glucose, 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 the disease. More severe reductions in brain glycolysis were also related to the expression of symptoms of Alzheimer’s disease during life, such as problems with memory.

 

While similarities between diabetes and Alzheimer’s have long been suspected, they have been difficult to evaluate, since insulin is not needed for glucose to enter the brain or to get into neurons. The authors tracked the brain’s usage of glucose by measuring ratios of the amino acids serine, glycine and alanine to glucose, allowing them to assess rates of the key steps of glycolysis. Results showed that the activities of enzymes controlling these key glycolysis steps were lower in Alzheimer’s cases compared to normal brain tissue samples. Furthermore, lower enzyme activity was associated with more severe Alzheimer’s pathology in the brain and the development of symptoms.

 

Next, the authors used proteomics — the large-scale measurement of cellular proteins — to tally levels of GLUT3, a glucose transporter protein, in neurons. They found that GLUT3 levels were lower in brains with Alzheimer’s pathology compared to normal brains, and that these levels were also connected to the severity of tangles and plaques. Finally, the team checked blood glucose levels in study participants years before they died, finding that greater increases in blood glucose levels correlated with greater brain glucose levels at death.

 

According to the authors, the findings point to a novel mechanism that could be targeted in the development of new treatments to help the brain overcome glycolysis defects in Alzheimer’s disease. However, the authors cautioned that it is not yet completely clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of Alzheimer’s disease symptoms or the speed of disease progression. The next steps for the authors include studying abnormalities in other metabolic pathways linked to glycolysis to determine how they may relate to Alzheimer’s pathology in the brain.

 

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