May 4, 2020Neurology
According to a study published in Nature Medicine (13 April 2020), in the largest study to date of proteins related to Alzheimer's disease (AD), disease-specific proteins and biological processes have been identified 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 AD pathology and cognitive impairment.
The study, part of the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD), 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. The study 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 AD. Overall, the study identified groups (or modules) of proteins that reflect biological processes in the brain. The authors then analyzed how the protein modules relate to various pathologic and clinical features of AD and other neurodegenerative disorders. Study results demonstrated changes in proteins related to glucose metabolism and an anti-inflammatory response in glial cells in brain samples from both people with AD, as well as in samples from individuals with documented brain pathology who were cognitively normal. These results suggest that the anti-inflammatory processes designed to protect nerve cells may have been activated in response to the disease.
The authors also set out to reproduce the findings in cerebrospinal fluid. Results showed 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 AD. Many of these proteins were also elevated in people with preclinical AD, 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 AD, suggesting that the biological processes reflected by these protein families are involved in the actual disease process.
In a previous study, the authors 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.
Brain tissue samples came from autopsy of participants in Alzheimer's disease research centers and several epidemiologic studies across the country, including the Baltimore Longitudinal Study of Aging (BLSA), Religious Orders Study (ROS) and Memory and Aging Project (MAP), and Adult Changes in Thought (ACT). The brain collections also contained samples from individuals with six other neurodegenerative disorders as well as samples representing normal aging, which enabled the discovery of molecular signatures specific for Alzheimer's. Cerebrospinal fluid samples were collected from study participants at the Emory Goizueta Alzheimer's Disease Research Center. These and other datasets are available to the research community through the AD Knowledge Portal, the data repository for the AMP-AD Target Discovery Program, and other NIA supported team-science projects operating under open science principles.