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Cerebrospinal Fluid Proteomics Reveals Biological Processes Involved in Alzheimer's Disease

NEW YORK – By profiling protein patterns in cerebrospinal fluid samples from individuals with or without Alzheimer's disease, researchers in the US and Iceland have uncovered new clues to biological processes behind the disease and its response to a proposed treatment.

"Cerebrospinal fluid is the most proximate biofluid to the brain in which to assess normal and abnormal brain physiology," senior author Erik Johnson, an Alzheimer's disease and neurology researcher at Emory University, and his colleagues wrote in Science Translational Medicine on Wednesday, noting that "multidimensional profiling of the [Alzheimer's disease cerebrospinal fluid] proteome … is a promising approach to further our understanding of [Alzheimer's disease] pathophysiology and develop biomarkers for this varied pathophysiology."

Using tandem mass tag mass spectrometry (TMT-MS) and SomaLogic's modified aptamer-based SomaScan 7000 assay, the researchers generated proteomic profiles for thousands of cerebrospinal fluid samples from 160 individuals with Alzheimer's disease and 140 unaffected individuals from cohorts in Iceland and the US.

The team also considered a few dozen cerebrospinal fluid samples collected during a Phase II clinical trial of atomoxetine (ATX), a norepinephrine reuptake inhibitor approved for treating attention deficit disorder that has been linked to enhanced metabolic activity in the brain and decreased tau protein levels in cerebrospinal fluid.

"The objective of this study was to characterize the proteomic changes that occur in [Alzheimer's disease cerebrospinal fluid]," the authors explained, "and use these changes to understand disease risk and treatment effects of ATX."

After their quality control steps, the investigators had data for 4,576 individual proteins, including 2,195 proteins profiled by TMT-MS and 3,649 proteins assessed with the SomaScan assay. Together, the proteins made it possible to tease out 10 cerebrospinal fluid clusters falling in three broader superclusters.

"These analyses demonstrated aspects of the [cerebrospinal fluid] proteome preferentially measured by each platform and illustrated that measurements of the same protein target can vary between platforms," the authors explained, noting that "[c]lustering of individuals based on their [cerebrospinal fluid] proteomic profiles revealed heterogeneity of pathological changes, not fully reflected by amyloid-beta and tau."

The team's subsequent analyses highlighted nearly three dozen protein co-expression modules that pointed to the apparent importance of processes such as glycolysis, autophagy, ubiquitination, and endocytosis in Alzheimer's disease.

The researchers also saw three protein modules associated with Alzheimer's cases marked by an APOE epsilon-4 risk variant. These modules included processes like oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology. They further identified a specific protein network module that appeared to be influenced by treatment with ATX.

In particular, the authors found that "abnormal elevations in the glycolysis [cerebrospinal fluid] module — the network module most strongly correlated to cognitive function — were reduced by ATX treatment."

Based on their findings so far, the researchers suggested that the cerebrospinal fluid proteomic strategy "holds promise to advance precision medicine approaches for Alzheimer's disease."