Dr Nicholas SeyfriedNicholas T. Seyfried, PhD
Data from a study of more than 2000 brains and approximately 400 cerebrospinal fluid (CSF) samples suggest that a number of disease-specific proteins and biological processes in Alzheimer disease brains may serve as therapeutic targets and fluid biomarkers.1

The study identified that glial biology—microglial biology, specifically—is likely a causal driver of Alzheimer pathogenesis, consistent with the results of other recent protein coexpression analyses of the disease. This work, conducted by Nicholas T. Seyfried, PhD, and colleagues from the Goizueta Alzheimer’s Disease Research Center at Emory University School of Medicine, is the largest proteomic study thus far on Alzheimer disease.

Using quantitative mass spectrometry and coexpression network analysis, the group identified a protein network module linked to glucose metabolism (Module 4; M4) to be significantly associated with Alzheimer pathology and cognitive impairment. “Programs that target this biology hold promise for Alzheimer drug therapy and biomarker development, especially those that target pro- and anti-inflammatory astrocytes and microglia,” the group wrote.

All told, the group assessed a network of 13 protein coexpression modules—or communities of proteins—were included in the network, ranging from 254 proteins (Module 1; M1) to 20 proteins (Module 13; M13). The study was conducted as part of the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) and funded by the National Institutes of Health's National Institute on Aging (NIA).  

"This is an example of how the collaborative, open science platform of AMP-AD is creating a pipeline of discovery for new approaches to diagnosis, treatment and prevention of Alzheimer's disease. This study exemplifies how research can be accelerated when multiple research groups share their biological samples and data resources," said Richard J. Hodes, MD, director, NIA, in a statement.2
 
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The group observed that the M4 module was enriched in genetic risk factors for Alzheimer and in microglia and astrocyte protein markers associated with an anti-inflammatory state, implying that the biological functions it represents serve a protective role in Alzheimer. Proteins from the M4 module were additionally elevated in cerebrospinal fluid in the early stages of the disease.

“Microglial protein markers that are increased in response to amyloid-β plaques but decreased in response to lipopolysaccharide—or markers of anti-inflammatory disease-associated microglia—were significantly enriched in the M4 module,” Seyfried et al. described, noting that markers of astrocytes were slightly more varied in the M4 module, with a majority of markers being shared between deleterious A1 and protective A2 phenotypes.

The M4 astrocyte/microglial metabolism module increased in asymptomatic AD, correlating most strongly with cognitive impairment, which Seyfried and colleagues noted is suggestive of early occurrence of these biological changes in the disease process with significant impact on the functions of progression to dementia.“An important observation is that AD genetic risk alleles, which are more likely to cause loss-of-function changes rather than gain-of-function changes, are enriched in the M4 module,” they noted.

Madhav Thambisetty, MD, PhD, investigator, and chief, Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, NIA, noted in a statement that the group has been researching the potential links between abnormalities in the way the brain metabolizes glucose and Alzheimer-related changes for some time.

“The latest analysis suggests that these proteins may also have potential as fluid biomarkers to detect the presence of early disease,” he said. Thambisetty and colleagues at Emory University had earlier identified a connection between issues in the process by which the brain breaks down glucose and the accumulation of amyloid plaques and tangles in the brain—as well as memory and cognitive problems.

“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 Suzana Petanceska, PhD, program director, AMP-AD Target Discovery Program, NIA, in a statement. “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.”
REFERENCES
1. Johnson ECB, Dammer EB, Duong DM, et al. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nature Med. 2020;26:769–780. doi: 10.1038/s41591-020-0815-6
2. Large-scale analysis links glucose metabolism proteins to Alzheimer's disease biology [press release]. Bethesda, MD: NIH/National Institute on Aging. Published April 14, 2020. Accessed May 21, 2020. sciencedaily.com/releases/2020/04/200413120031.htm