Researchers have made connections between proteins and genes associated with diseases to pinpoint particular cellular pathways that contribute to the onset and development of Alzheimer’s disease. They collected proteins from cerebrospinal fluid (CSF), which effectively reflects brain activity, and several of these proteins could serve as potential targets for treatment options.
Numerous genes have been identified as related to the onset of Alzheimer’s disease. However, the exact manner in which these genes might affect the issues associated with neurodegeneration is still somewhat unclear, primarily due to the difficulties of studying the brain of a living individual at a molecular level.
A research team from Washington University School of Medicine in St. Louis has, for the first time, linked proteins and genes related to disease using CSF collected from living patients, enabling them to identify specific cellular pathways tied to the emergence and progress of Alzheimer’s disease. The proteins derived from CSF offer valuable insights into brain activity, and many could be promising candidates for therapeutic interventions.
The research findings were published in Nature Genetics.
According to Carlos Cruchaga, PhD, the Barbara Burton and Reuben Morriss III professor of psychiatry and director of the NeuroGenomics and Informatics Center at WashU Medicine, utilizing CSF from patients marks a significant advance in such studies, as it likely represents the most effective means of obtaining pertinent samples to chart the network of protein activity, referred to as the proteome.
“Our objective is to discover genes linked to risk and those that provide protection, and to clarify their causal roles,” said Cruchaga. “To accomplish this, we need to explore data derived from humans. That’s why we opted for an extensive proteomic analysis of cerebrospinal fluid; we understand CSF serves as a reliable indicator of the disease’s pathology.”
Cruchaga noted that previous studies often relied on brain tissues obtained postmortem, which could only provide insights into the later phases of Alzheimer’s disease. Other research has investigated blood plasma, which does not specifically target the tissues involved in the disease.
In the last fifteen years, researchers investigating Alzheimer’s have expanded the number of genomic regions associated with the disease from 10 to almost 80. Despite knowing the gene or DNA region associated with the disease, linking an individual’s proteomic profile—indicating active proteins and their levels—to their genetic information creates a comprehensive picture of cellular behavior within the brain. By comparing CSF samples from Alzheimer’s patients to those without the disease, the team was able to pinpoint dysfunctional cellular pathways.
“Within a DNA region correlated with Alzheimer’s, multiple genes may exist, but we lack clarity on which gene is responsible for the condition,” stated Cruchaga. “Incorporating protein analysis allows us to identify the gene driving the association, to clarify the molecular pathway involved, and to discover new protein-to-protein interactions that may not have been possible otherwise.”
Cruchaga and his team benefited from an extensive database made available through the Knight-ADRC and the Dominantly Inherited Alzheimer Network (DIAN) at WashU Medicine, as well as additional studies conducted by their collaborators. These resources enabled the research team to analyze genetic data and CSF samples from 3,506 individuals, which included healthy participants and those diagnosed with Alzheimer’s.
They cross-referenced the proteomic information from CSF samples with existing studies that had already pinpointed genomic areas linked to Alzheimer’s disease. This analysis identified 1,883 proteins out of the 6,361 documented in the CSF proteomic atlas. The researchers employed three different established statistical methods, allowing them to accurately identify genes and proteins involved in the biological pathways related to the disease. Through this process, they determined that 38 proteins likely contribute to Alzheimer’s progression, with 15 of these being potential targets for medication.
“The novelty and strength of this analysis is that we’ve identified proteins that alter risk,” Cruchaga commented. “Now that we’ve established the causal pathways, we can discern their implications within the brain.”
The implications of this study for understanding Alzheimer’s and developing treatments are substantial. Cruchaga believes that CSF proteomics holds vast potential for uncovering information related to various neurological disorders, from Parkinson’s disease to schizophrenia.
“The strength of this methodology is that once you create a map of genetic variants alongside protein levels, the approach can be applied to any disease,” he explained.
Proteins are not the sole factor in unlocking these conditions found within the CSF. Cruchaga is also exploring the role of metabolites—substances released by cells during the process of breaking down compounds, which are also present in CSF. In a separate study, also published in Nature Genetics, he and his team exhibited the potential of this line of research, revealing associations between specific metabolites and conditions such as Parkinson’s disease, diabetes, and dementia.
