A new study leveraging cerebrospinal fluid (CSF) proteomics has identified 34 protein modules associated with Alzheimer's disease (AD) phenotypes, shedding light on the intricate mechanisms driving the disease and potential therapeutic interventions. The research, published in Science Translational Medicine, combined two proteomic techniques to analyze over 4,000 proteins in CSF samples, linking specific protein co-expression modules to AD-related biomarkers and cognitive impairment.
ApoE4's Influence on Protein Pathways
The study, led by Erik Johnson of Emory University, delved into the pathways influenced by the ApoE4 genotype, a major genetic risk factor for AD. The analysis revealed associations between ApoE4 and proteins involved in oxidative stress, mitochondrial function, and neddylation, a protein modification process similar to ubiquitination. Notably, these protein networks were also predictive of future AD development in serum samples from cognitively normal individuals.
"This paper represents yet another proteomics tour de force from the Emory group," commented Russell Swerdlow of Kansas University Medical Center, highlighting the study's emphasis on changes in mitochondrial and glycolysis modules. He also noted the interconnectedness of metabolism, inflammation, and proteostasis in brain health and disease.
Atomoxetine's Impact on Glucose Metabolism
The researchers also investigated the effects of atomoxetine, a norepinephrine reuptake inhibitor approved for ADHD, on the CSF proteome. A Phase 2 clinical trial at Emory, with a cross-over design involving 39 participants with mild cognitive impairment (MCI) due to AD, showed that atomoxetine modulated several protein modules. While the drug did not improve cognition, it increased CSF norepinephrine levels, reduced CSF total tau and p-tau181, and enhanced brain glucose metabolism as measured by FDG-PET, consistent with previous findings (Levey et al., 2021).
Specifically, atomoxetine reduced the expression of a 65-protein glycolysis/redox module that was elevated in AD. However, the impact of these changes remains unclear, as Johnson noted that it is uncertain whether reducing glycolysis proteins is beneficial or detrimental in the context of AD.
Proteomic Heterogeneity in Alzheimer's
Unbiased proteomic analysis revealed significant heterogeneity among individuals, even within biomarker-defined groups. Participants were divided into 10 groups based on their proteomic profiles, with only one group showing uniform biomarker levels of amyloid-beta and tau. This highlights the complexity of AD and the limitations of relying solely on amyloid and tau biomarkers for diagnosis and treatment.
"We’re defining the disease based on Aβ and tau, but so many other processes are contributing to the cognitive decline that people are dealing with," Johnson explained. "We are trying to peel back all those layers to understand the process."
