Researchers at Washington University School of Medicine in St. Louis have made a groundbreaking discovery in Alzheimer’s disease research. For the first time, they’ve linked specific disease-related proteins and genes, uncovering the cellular pathways responsible for the development and progression of Alzheimer’s. This was made possible by analyzing cerebrospinal fluid (CSF) collected from living patients, offering insights into brain activity that were previously difficult to obtain.
The study, published in Nature Genetics, marks a significant step forward in Alzheimer’s research. CSF, which surrounds the brain and spinal cord, provides a direct window into brain function and can reveal crucial details about the disease. According to Carlos Cruchaga, PhD, a leading researcher and director of the NeuroGenomics and Informatics Center at Washington University, using CSF is a major improvement over older methods, which relied on postmortem brain tissue or blood plasma—neither of which provided as much relevant information about the disease’s progression.
Over the past 15 years, scientists have identified nearly 80 genetic regions linked to Alzheimer’s, up from just 10. However, understanding which genes are responsible for the disease is only the beginning. By analyzing the proteome— the collection of proteins active in the brain—scientists can gain a more complete picture of Alzheimer’s at the cellular level. In this study, researchers compared CSF samples from individuals with and without Alzheimer’s disease to pinpoint which cellular pathways are disrupted.
“The challenge has always been that many genes linked to Alzheimer’s disease are located in the same region of DNA, making it difficult to identify the specific gene causing the condition,” Cruchaga explained. “By adding proteins to the analysis, we can better understand the gene driving the disease, the molecular pathway involved, and identify new protein interactions.”
Using data from large-scale studies, including the Knight-ADRC and the Dominantly Inherited Alzheimer Network (DIAN), the research team analyzed the CSF samples of 3,506 individuals, including both healthy people and those with Alzheimer’s. They focused on 1,883 proteins from a total of 6,361 identified in the CSF proteomic atlas. Through rigorous statistical analysis, the team identified 38 proteins that may play a causal role in Alzheimer’s progression, 15 of which could be targeted by existing medications.
“The strength of this study is that we’ve pinpointed proteins that directly influence the risk of Alzheimer’s,” Cruchaga said. “By understanding these key proteins and their pathways, we can better map the disease’s progression in the brain.”
The implications of this research are vast. Not only does it provide valuable insights into Alzheimer’s treatment, but Cruchaga believes the same approach could be applied to other neurological conditions, such as Parkinson’s disease and schizophrenia. “Once we have a comprehensive atlas of genetic and protein data, it can be applied to any neurological disease,” he said.
In addition to proteins, Cruchaga is also exploring the potential of metabolites—substances released by cells during normal metabolic processes. In a related study, also published in Nature Genetics, his team identified links between specific metabolites and conditions like Parkinson’s disease, diabetes, and dementia, further highlighting the potential of CSF analysis in understanding neurological diseases.
This study marks an important step toward unlocking the mysteries of Alzheimer’s and other neurological conditions, offering hope for more effective treatments in the future.
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