Researchers use cerebrospinal fluid to unlock pathways in Alzheimer’s disease

A large number of genes have been linked to the development of Alzheimer’s disease. However, how these genes in particular may influence the progression of neurodegeneration remains something of a black box, partly because of the challenges of examining a living patient’s brain in molecular detail.

Using cerebrospinal fluid (CSF) collected from living patients, a team of researchers from Washington University School of Medicine in St. Louis has linked together disease-related proteins and genes for the first time to identify specific cellular pathways responsible for onset and progression of Alzheimer’s disease. Because these proteins were collected from cerebrospinal fluid, they are a good measure of activity in the brain, and several of them could be potential targets for therapies.

The findings are available in Nature genetics.

Using cerebrospinal fluid from patients is a step forward for such studies and may be the best way to obtain relevant samples that help map the constellation of protein activity known as the proteome, according to Carlos Cruchaga, PhD, Barbara Burton and Reuben Morriss. III professor of psychiatry and director of the NeuroGenomics and Informatics Center at WashU Medicine.

Our goal is to identify risk-related and protective genes, as well as identify the causal role they play. To do that, we need to study human-derived data. That’s why we decided to conduct a large cerebrospinal fluid proteomic study, because we know that CSF is a good representation of the pathology of the disease.”

Carlos Cruchaga, PhD, the Barbara Burton and Reuben Morriss III Professor of Psychiatry and director of the NeuroGenomics and Informatics Center at WashU Medicine

Cruchaga explained that similar studies relied on brain tissue collected postmortem and therefore only provide information about the later stages of Alzheimer’s disease. Other studies have looked at blood plasma, which is not specific to the tissues affected by the disease.

Over the past fifteen years of research into Alzheimer’s disease, scientists have increased the number of regions of our genome known to be associated with the disease from 10 to nearly 80. Knowing the gene or region of DNA associated with the disease is associated with, however, is only the first step. Linking an individual’s proteomic profile – i.e. which proteins are active and to what extent – ​​to their genetic code provides a holistic view of the cellular activities in the brain. By comparing CSF samples from people with and without Alzheimer’s disease, the researchers were able to identify which cellular pathways are dysfunctional.

“Sometimes within a region of DNA known to be associated with Alzheimer’s disease, there are many genes, and we don’t know which of those genes cause the medical condition,” Cruchaga said. “By adding the proteins to the analysis, we can determine the gene driving the association, determine the molecular pathway they are part of, and identify novel protein-to-protein interactions that would not otherwise be possible.”

Cruchaga and his collaborators had access to a rich database of information through the Knight-ADRC and the Dominantly Inherited Alzheimer Network (DIAN), which are based at WashU Medicine, as well as other research through their collaborators. These studies were also able to provide the genetic information and CSF samples of 3,506 individuals, both healthy donors and people with Alzheimer’s disease.

The team compared proteomic data from the CSF samples with existing studies that had identified regions of the genome associated with Alzheimer’s disease. Through this process, they narrowed down to 1,883 proteins out of 6,361 in the CSF proteomic atlas. The researchers used three different established statistical analyzes that can identify high-confidence genes and proteins that are part of the biological pathways leading to the disease. Using this technique, they determined that 38 proteins likely have a causal effect on the progression of Alzheimer’s; Fifteen of these can be targeted by drugs.

“The novelty and power of this analysis is that we have defined proteins that modify risk,” Cruchaga said. “So now that we have the causal steps, we can determine where the steps lead in the brain.”

The direct implications for understanding and developing treatments for Alzheimer’s disease from this study are significant, but Cruchaga said he believes CSF proteomics could provide a wealth of information for many neurological disorders ranging from Parkinson’s disease to schizophrenia .

“That’s the power of this approach: once you have an atlas of genetic variants and that of the protein levels, you can apply it to any disease,” he said.

Proteins aren’t the only key to unlocking these conditions in the cerebrospinal fluid. Cruchaga is also investigating the potential of metabolites – substances released by cells when breaking down other compounds as part of their routine processes that are also found in CSF. In a separate paper, also published in Nature Genetics, he and his collaborators demonstrated the promise of this approach and reported associations between specific metabolites and conditions including Parkinson’s disease, diabetes and dementia.