Increased Breakdown of Glucose in Brain Linked to Severity of Alzheimer’s Disease

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Highlights:

• Abnormalities in the way the brain breaks down glucose has now been linked with Alzheimer’s disease pathology and symptoms
• Alzheimer’s disease pathology is characterized by beta-amyloid protein plaques and neurofibrillary tangles
• Lower rates of glycolysis (breakdown of glucose) have been correlated to more plaques and tangles in the brains of Alzheimer’s patients and with the onset of disease symptoms.

One of the world’s longest-running scientific studies of human aging called the Baltimore Longitudinal Study of Aging (BLAS) has come out with an analysis connecting the breakdown of glucose (glycolysis) in the brain to the pathology or disease formation of Alzheimer’s disease (AD), as well as to the onset of AD’ outward symptoms. Alzheimer’s disease pathology is characterized by signature beta-amyloid protein plaques and neurofibrillary tangles in the brain.

The study published in Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association, says that there is evidence linking the severity of the abnormalities in the brain’s glycolysis to the severity of Alzheimer’s pathology. The research was supported by the National Institute on Aging (NIA), part of the National Institutes of Health.

The study was led by Madhav Thambisetty, M.D., Ph.D., investigator and chief of the Unit of Clinical and Translational Neuroscience in the NIA’s Laboratory of Behavioral Neuroscience,

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Baltimore Longitudinal Study of Aging (BLAS)

Brain tissue samples from participants were analyzed at autopsy and the neurological, physical and psychological data on participants were studied over several decades.

Participants belonged to three different disease status.

• Healthy individuals who served as controls
• Individuals who did not have any symptoms of AD during life but whose brain post-mortem revealed significant levels of Alzheimer’s pathology
• Individuals with Alzheimer’s symptoms during life and with confirmed AD pathology in the brain at death

AD pathology is more pronounced in areas like the frontal and temporal cortex and lesser in the cerebellum. When researchers measured glucose levels in these different brain regions they found distinct abnormalities in glycolysis. Since glycolysis is the primary process by which the brain breaks down glucose, lower rates of glycolysis would directly correlate to higher levels of glucose in the brain.

Results showed that -

• Lower rates of glycolysis correlated to more severe plaques and tangles found in the brains of people with the disease.
• When brain glycolysis reduces even more, it could have a direct effect on the expression of symptoms of Alzheimer’s disease during life, such as problems with memory.
• Activities of enzymes (amino acids serine, glycine and alanine) controlling the key glycolysis steps were lower in Alzheimer’s cases compared to normal brain tissue samples
• Lower enzyme activity was associated with more severe Alzheimer’s pathology in the brain and the development of symptoms.
• Large-scale measurement of cellular proteins (proteomics) revealed that the levels of GLUT3, a glucose transporter protein, in neurons were lower in brains with Alzheimer’s pathology compared to normal brains.
• Greater increases in blood glucose levels in study participants taken years before they died 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,” said NIA Director Richard J. Hodes, M.D. “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.”

“These 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,” said Thambisetty.

Future plans for Thambisetty and his team include studying other metabolic pathways linked to glycolysis to determine if they show any abnormalities and how that could relate to Alzheimer’s pathology in the brain.

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Alzheimer’s disease (AD)

Alzheimer’s disease is a chronic neurodegenerative disease and is the cause of 60% to 70% of cases of dementia. The earliest symptom of the disease is difficulty in remembering recent events. Advanced Alzheimer’s can include problems with language, easily getting lost, mood swings, lack of motivation, not able to take care of themselves, and behavioral issues. The patients later withdraw from family and society and lose bodily functions; this ultimately leads to death. The average life expectancy of AD patients following diagnosis is three to nine years.

References:

1. “Evidence for brain glucose dysregulation in Alzheimer’s disease” by Yang An, Vijay R. Varma, Sudhir Varma, Ramon Casanova, Eric Dammer, Olga Pletnikova, Chee W. Chia, Josephine M. Egan, Luigi Ferrucci, Juan Troncoso, Allan I. Levey, James Lah, Nicholas T. Seyfried, Cristina Legido-Quigley, Richard O’Brien, and Madhav Thambisetty in Alzheimer’s & Dementia:. Published online October 19 2017 doi:10.1016/j.jalz.2017.09.011
2. Alzheimer’s disease - (https://en.wikipedia.org/wiki/Alzheimer’s_disease)

Source-Medindia