With one of the largest segments of the population settling into prime Alzheimer’s disease (AD) age ranges, it is essential, now more than ever, to identify new biomarkers and treatment targets for this neurodegenerative disorder. As such, a team of investigators led by scientists at Emory University has identified sets of proteins that regulate glucose metabolism, together with proteins related to a protective role of astrocytes and microglia, that are strongly associated with Alzheimer’s pathology and cognitive impairment.

Findings from the new study were published recently in Nature Medicine through an article titled, “Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation.” In this largest study to date of proteins related to Alzheimer’s disease, researchers measured the levels and analyzed 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.

“This is an example of how the collaborative, open science platform of Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) is creating a pipeline of discovery for new approaches to diagnosis, treatment, and prevention of Alzheimer’s disease,” said the National Institutes of Aging (NIA) director Richard J. Hodes, MD. “This study exemplifies how research can be accelerated when multiple research groups share their biological samples and data resources.”

Researchers analyzed patterns of protein expression in more than 2,000 human brains and nearly 400 cerebrospinal fluid samples from both healthy people and those with Alzheimer’s disease. Then the scientists 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 might have been activated in response to the disease.

“We used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD,” the authors wrote. “A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents, serve a protective role in AD.”

Additionally, the investigators 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.

“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,” explained study co-author Madhav Thambisetty, MD, PhD, investigator and chief of the clinical and translational neuroscience section in the NIA’s Laboratory of Behavioral Neuroscience. “The latest analysis suggests that these proteins may also have potential as fluid biomarkers to detect the presence of early disease.”

In a previous study, Thambisetty and colleagues, in collaboration with the Emory 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,” concluded Suzana Petanceska, PhD, program director at NIA overseeing the AMP-AD Target Discovery Program. “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.”

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