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Alzheimer's Disease Proteomic Study Reveals Potential New Biomarkers, Drug Targets

NEW YORK – Using a proteomic approach, a team lead by researchers at Emory University School of Medicine has discovered new protein expression markers for Alzheimer's disease in brain and cerebrospinal fluid (CSF), providing a look at the role that energy metabolism may play in the trajectory of the disease.

"Our results highlight the importance of inflammation, sugar metabolism, mitochondrial function, synaptic function, RNA-associated proteins, and glia in the pathogenesis of [Alzheimer's disease] and provide a robust framework for future proteomic and multi-omic studies on [Alzheimer's disease] brain and biofluid biomarkers," co-corresponding authors Nicholas Seyfried and Allan Levey, both researchers at Emory, and their co-authors reported.

With the help of quantitative mass spectrometry and network analyses focused on proteins that are co-expressed, the researchers tallied proteomic patterns in thousands of brain samples from individuals with or without Alzheimer's disease. Their findings, appearing in Nature Medicine on Monday, highlighted a microglia- and astrocyte-related protein network subsequently found to have higher-than-usual expression in cerebrospinal fluid samples from individuals with early stages of Alzheimer's disease.

"A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with [Alzheimer's disease] pathology and cognitive impairment," the authors reported. "This module was enriched in [Alzheimer's disease] 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 [Alzheimer's disease]."

Though past research has shown that amyloid-beta plaque and neurofibrillary tangles in the brain's neocortex are key features in Alzheimer's disease, the team explained, there is still much to be learned about the biological changes in the brain and CSF as the neurodegenerative disease develops and takes hold.

"Communities of co-expressed proteins can be linked to disease processes and the most strongly correlated proteins or 'hubs' within these co-expression modules are enriched in key drivers of disease pathogenesis," the authors explained. "Therefore, targeting hubs within protein co-expression modules most related to disease biology is a promising approach for drug and biomarker development."

Through a consortium called the Accelerating Medicine Partnership for Alzheimer's Disease (AMP-AD), the researchers performed quantitative mass spec-based proteomic profiling on more than 2,000 postmortem brain samples — representing the dorsolateral prefrontal cortex or temporal cortex and precuneus region of the brain — from 453 individuals with Alzheimer's disease and as many unaffected controls, enrolled through several prior studies.

The team's analysis highlighted a set of proteins that appeared to contribute to sugar metabolism in glial cells from the central nervous system, particularly microglia and astrocytes, hinting that altered responses of these cells to amyloid plaques may impact Alzheimer's disease development and progression.

With isobaric multiplex tandem mass tag-based analyses on hundreds of individuals with or without Alzheimer's disease from two more cohorts, the researchers saw signs that this protein co-expression module had higher-than-usual expression in CSF samples from individuals with cognitive impairment and those who were symptom-free but went on to develop the condition.

"A key finding from our proteomic study is that glial biology — and microglial biology in particular — is a likely causal driver of [Alzheimer's disease] pathogenesis," the authors suggested, noting that "[p]rograms that target this biology hold promise for [Alzheimer's disease] drug therapy and biomarker development, especially those that target pro- and anti-inflammatory astrocytes and microglia."

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