In the largest study to date of proteins related to Alzheimer's disease, a team of researchers has identified disease-specific proteins and biological processes that could be developed into both new treatment targets and fluid biomarkers. The findings suggest that sets of proteins that regulate glucose metabolism, together with proteins related to a protective role of astrocytes and microglia -- the brain's support cells -- are strongly associated with Alzheimer's pathology and cognitive impairment.

The study involved measuring the levels and analyzing the expression patterns of more than 3,000 proteins in a large number of brain and cerebrospinal fluid samples collected at multiple research centers across the United States and published in Nature Medicine.

The research team analyzed patterns of protein expression in more than 2,000 human brain and nearly 400 cerebrospinal fluid samples from both healthy people and those with Alzheimer's disease. The paper's authors identified groups (or modules) of proteins that reflect biological processes in the brain.

The researchers then analyzed how the protein modules relate to various pathologic and clinical features of Alzheimer's and other neurodegenerative disorders. They saw changes in proteins related to glucose metabolism and an anti-inflammatory response in glial cells in brain samples from both people with Alzheimer's as well as in samples from individuals with documented brain pathology who were cognitively normal. This suggests, the researchers noted, that the anti-inflammatory processes designed to protect nerve cells may have been activated in response to the disease.

The researchers also set out to reproduce the findings in cerebrospinal fluid. The team found that, just like with brain tissue, the proteins involved in the way cells extract energy from glucose are increased in the spinal fluid from people with Alzheimer's. Many of these proteins were also elevated in people with preclinical Alzheimer's, i.e., individuals with brain pathology but without symptoms of cognitive decline. Importantly, the glucose metabolism/glial protein module was populated with proteins known to be genetic risk factors for Alzheimer's, suggesting that the biological processes reflected by these protein families are involved in the actual disease process.

In a previous study, the researchers, found a connection between abnormalities in how the brain breaks down glucose and the amount of the signature amyloid plaques and tangles in the brain, as well as the onset of symptoms such as problems with memory.

"This large, comparative proteomic study points to massive changes across many biological processes in Alzheimer's and offers new insights into the role of brain energy metabolism and neuroinflammation in the disease process," said the author. "The data and analyses from this study has already been made available to the research community and can be used as a rich source of new targets for the treatment and prevention of Alzheimer's or serve as the foundation for developing fluid biomarkers."

https://www.nia.nih.gov/news/large-scale-analysis-links-glucose-metabolism-proteins-brain-alzheimers-disease-biology

https://www.nature.com/articles/s41591-020-0815-6