Understanding how genes influence Alzheimer’s disease has long challenged researchers, who could only study brain tissue after a patient’s death. Now, scientists at Washington University School of Medicine in St. Louis have pioneered a method to track the disease in living patients by analyzing their cerebrospinal fluid, identifying 38 proteins that could lead to new treatments.
Journal: Nature Genetics, November 11, 2024, DOI: 10.1038/s41588-024-01972-8 | Reading time: 4 minutes
From Genetic Links to Cellular Pathways
“Our goal is to identify risk-linked and protective genes, and also identify the causal role they play,” explains Carlos Cruchaga, PhD, director of the NeuroGenomics and Informatics Center at WashU Medicine. “That is why we decided to do a large proteomic study of cerebrospinal fluid, because we know that CSF is a good representation of the pathology of the disease.”
The past decade has seen the number of genetic regions linked to Alzheimer’s grow from 10 to nearly 80. But knowing these genetic connections was only the first step. By examining cerebrospinal fluid from 3,506 individuals – both healthy donors and those with Alzheimer’s – researchers could observe how genes affect protein activity in living brains.
Identifying Treatment Targets
Through detailed analysis of CSF samples, the team identified 1,883 relevant proteins out of 6,361 in their atlas. Using three established statistical methods, they pinpointed 38 proteins likely causing Alzheimer’s progression. Most significantly, 15 of these proteins can be targeted by medications.
“The novelty and the strength of this analysis is that we have defined proteins that modify risk,” Cruchaga notes. “So now that we have the causal steps, we can establish where the steps are leading to in the brain.”
Beyond Alzheimer’s: A New Research Frontier
This breakthrough method has implications beyond Alzheimer’s. “That’s the power of this approach – once you have an atlas of genetic variants, and that of the protein levels, you can apply this to any disease,” says Cruchaga. The technique could help decode other neurological conditions, from Parkinson’s disease to schizophrenia.
Glossary
- Cerebrospinal fluid (CSF): Clear fluid surrounding the brain and spinal cord that reflects brain chemistry
- Proteome: Complete set of proteins expressed in a biological system
- Genetic variants: Different versions of genes that can influence disease risk
- Neurodegeneration: Progressive loss of nerve cell function
- Molecular pathway: Series of interactions between proteins that lead to cell changes
Test Your Knowledge
1. What key advantage does cerebrospinal fluid analysis offer over traditional research methods?
It allows researchers to study disease progression in living patients rather than having to wait for post-mortem tissue samples.
2. How many potential drug targets did the research identify?
The study found 15 proteins that can be targeted by medications out of the 38 proteins identified as having causal effects.
3. What was the scale of the study in terms of participants?
The study analyzed cerebrospinal fluid samples from 3,506 individuals, including both healthy donors and Alzheimer’s patients.
4. How might this research method impact other diseases?
The same approach of mapping genetic variants and protein levels could be applied to study other neurological conditions like Parkinson’s disease and schizophrenia.
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