Possible druggable targets and biomarkers for Alzheimer’s

Emory-led research links glucose metabolism proteins in the brain to Alzheimer's disease biology

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ATLANTA—When it comes to glucose in pharma/biotech research and development and in clinical care, the first thing that pops into most minds is diabetes, but of course glucose is involved in all sorts of other bodily processes, both in healthy states and pathological ones. And the latest reminder of that comes from National Institutes of Health (NIH)-supported research led by Drs. Erik C.B. Johnson, Nicholas T. Seyfried and Allan Levey at the Emory University School of Medicine in Atlanta, in which a large-scale analysis they conducted links glucose metabolism proteins in the brain to Alzheimer’s disease biology.
As noted in a story posted on the NIH website by Joe Balintfy at NIH’s National Institute on Aging (NIA), which funded the research, “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, 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. This research was published April 13 in Nature Medicine under the title “Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation.”
To conduct the research, the Emory 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, which included Dr. Madhav Thambisetty, investigator and chief of the Clinical and Translational Neuroscience Section in the NIA’s Laboratory of Behavioral Neuroscience, 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.
As noted by the authors in the abstract for their published paper, “Our understanding of Alzheimer’s disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. 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. “
“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,” Thambisetty said. “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 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,” commented NIA Director Dr. Richard J. Hodes. “This study exemplifies how research can be accelerated when multiple research groups share their biological samples and data resources.”
Added Dr. Suzana Petanceska, program director at NIA overseeing the AMP-AD Target Discovery Program: “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. 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.”
In other recent news out of the NIA on Alzheimer’s disease research, the institute says that an APOE ε2 gene variant “packs a protective punch” against the disease.
As noted in a news release from the NIA, “When it comes to the APOE gene and Alzheimer’s disease, the risk-increasing APOE ε4 variant often takes center stage, but there’s much more to the APOE genetic risk story. The APOE ε2 variant appears to lower risk, and having two copies of this variant may lower risk even more than previously thought.”
A team of researchers wanted to better understand the role of APOE ε2 in Alzheimer’s disease risk. They calculated risk estimates based on data from 4,018 autopsy-confirmed Alzheimer’s dementia cases and 989 controls obtained through the NIA-funded Alzheimer’s Disease Genetics Consortium (ADGC). As expected, only a small number of the cases (24) had two copies of APOE ε2, but, compared with other genotypes, those with two copies were much less likely to have Alzheimer’s disease. Among the autopsy-confirmed cases, individuals with two copies of ε2 had a 66-percent risk reduction compared with people with one copy of ε2 and one copy of ε3, an 87-percent risk reduction compared to people with two copies of ε3, and a 99.6-percent risk reduction compared to people who had two copies of ε4.
The researchers also calculated risk estimates in an ADGC cohort of 23,857 participants (10,430 probable Alzheimer’s dementia cases and 13,426 controls). Two copies of APOE ε2 were still associated with a lower risk in this group, but the risk was not as low as in the autopsy-confirmed cases. The researchers attribute this to the fact that the autopsy-confirmed cases didn’t include any instances of misdiagnoses and suggest that the lower risk estimates seen in the neuropathologically confirmed sample may mean an even stronger protective effect from two copies of APOE ε2 than previously found.
In addition, those with two copies of APOE ε2 or one copy of APOE ε2 and one copy of APOE ε3 who did develop Alzheimer’s disease had a later age of onset and lower levels of amyloid-beta plaques and tau tangles, supporting previously known effects of APOE genotypes on these hallmarks of Alzheimer’s disease.
Findings point to the importance of clarifying the effect of APOE genotypes on Alzheimer’s pathology and exploring this avenue for potential treatments and preventions. For example, future research might investigate how to replicate the protective effects through gene editing or protein modification.

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