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Research has identified numerous genes associated with Alzheimer’s disease, yet the precise mechanisms by which these genes influence neurodegeneration remain largely unexplained. This lack of clarity stems partly from the difficulties in studying the brain’s molecular details in living patients.
In an innovative study, researchers at Washington University School of Medicine in St. Louis have utilized cerebrospinal fluid (CSF) from living individuals to establish connections between disease-related proteins and genes, thereby pinpointing specific cellular pathways involved in the development and advancement of Alzheimer’s. The proteins extracted from CSF serve as reliable indicators of brain activity, indicating potential therapeutic targets.
The comprehensive results of this research have been published in Nature Genetics.
According to Carlos Cruchaga, PhD, a professor of psychiatry and director of the NeuroGenomics and Informatics Center at WashU Medicine, the integration of CSF samples marks a significant advancement in the field. “Our objective is to uncover genes associated with both risk and protection while understanding their underlying causal roles,” Cruchaga explained. “By conducting an extensive proteomic study using CSF, we can effectively represent the disease’s pathology.”
Previous studies have primarily relied on postmortem brain tissues, which only shed light on the later stages of Alzheimer’s. In contrast, blood plasma studies lack specificity regarding affected brain tissues.
Over the last 15 years, the number of genomic regions linked to Alzheimer’s has expanded dramatically from 10 to nearly 80. However, identifying a gene associated with the disease is just a starting point; the true challenge lies in linking an individual’s proteomic profile—i.e., the active proteins and their concentrations—to their genetic makeup. This process offers a comprehensive understanding of the cellular dynamics in the brain. By comparing CSF samples from individuals with and without the disease, researchers can discern dysfunctional cellular pathways.
“Within a DNA region associated with Alzheimer’s, multiple genes may be present, and the specific gene driving the condition remains unclear,” Cruchaga noted. “By incorporating protein analysis, we can clarify which gene is influential, the molecular pathways involved, and recognize novel protein interactions that would otherwise go undetected.”
Collaborating with the Knight-ADRC and the Dominantly Inherited Alzheimer Network (DIAN) at WashU Medicine, Cruchaga’s team had access to extensive databases that provided the genetic information and CSF samples from 3,506 participants, including both healthy individuals and those with Alzheimer’s.
Through cross-referencing proteomic data with established studies pinpointing genomic regions related to Alzheimer’s, the researchers identified 1,883 proteins from a total of 6,361 in the CSF proteomic atlas. Utilizing three established statistical methods, they highlighted 38 proteins likely to play causal roles in Alzheimer’s progression, with 15 of these identified as potential drug targets.
Cruchaga emphasized the significance of their findings: “The novelty of our analysis lies in defining proteins that modify risk. Now that we understand the causal mechanisms, we can trace their implications in the brain.”
The potential ramifications of this study for advancing Alzheimer’s understanding and treatment are profound. According to Cruchaga, the principles of CSF proteomics could provide valuable insights for a range of neurological disorders, including Parkinson’s disease and schizophrenia. “The versatility of this method is striking—once you have a genetic and protein-level atlas, you can apply it to various diseases,” he stated.
Aside from proteins, the study also explores the role of metabolites—substances produced by cellular breakdown processes that are detectable in CSF. In a related publication, also in Nature Genetics, Cruchaga and his team showcased the potential of this approach, revealing connections between certain metabolites and conditions like Parkinson’s disease, diabetes, and dementia.
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