Summary: Researchers discovered alcohol use disorder (AUD) and Alzheimer's disease (AD) exhibit similar patterns of gene dysregulation, hinting that alcohol consumption may hasten Alzheimer's progression. By analyzing gene expression across individual brain cells, the team found shared disruptions in inflammation, cell signaling, and blood vessel functions in both disorders.
These findings highlight AUD as a potential risk factor for AD and could lead to new therapeutic targets. The research underscores the need to consider alcohol's impact in Alzheimer's prevention and treatment strategies. Future studies aim to validate findings with larger AUD datasets.
Nearly 7 million Americans have Alzheimer's disease, and this number is predicted to double by 2060. While aging and genetic predisposition are the most important risk factors for Alzheimer's, epidemiological studies suggest that lifestyle factors including alcohol use could also impact disease onset and progression.
Now, Scripps Research scientists have shown that Alzheimer's and alcohol use disorder (AUD) are associated with similarly altered gene expression patterns in the brain, supporting the idea that alcohol use may promote Alzheimer's disease progression.
The study, published in eNeuro on September 19, 2024, could inform future preventative and treatment strategies.
"We found several cell-type-specific genes and pathways that are dysregulated in both Alzheimer's disease and alcohol, which supports the hypothesis that alcohol use disorder can accelerate Alzheimer's disease progression by impinging on some of the same molecular mechanisms that are affected by Alzheimer's," says senior author Pietro Paolo Sanna, MD, a professor in the Immunology and Microbiology Department at Scripps Research.
"By understanding these dysregulations with this level of molecular detail, we can understand what's causing these diseases, and we can also identify targets that could be used therapeutically."
This is the first time researchers have used single cell transcriptomics -- a method that analyzes gene expression within individual cells by sequencing their RNA -- to compare changes associated with Alzheimer's disease and AUD in different populations of human brain cells.
The study builds upon previously published research in the Sanna lab that showed that excessive alcohol consumption accelerates Alzheimer's progression in mice that are genetically predisposed to the disease.
To examine cell-specific gene expression changes, the team analyzed RNA sequencing data from hundreds of thousands of individual brain cells from 75 patients with varying stages of Alzheimer's disease (early, intermediate or advanced), and 10 patients without Alzheimer's.
Then, they compared this Alzheimer's gene expression data with previously published RNA sequencing data from individuals with AUD.
They showed that both AUD and Alzheimer's are associated with similar gene expression changes in the brain, including upregulation of inflammatory genes and pathways, disruption to cell signaling and cell-death-related pathways, and changes to blood vessel cells.
"What we've presented here is a differential analysis of two disorders that cause cognitive decline," says first author Arpita Joshi, Ph.D., a staff scientist in Sanna's lab at Scripps Research.
"It deepens our understanding of Alzheimer's disease and what the three clinically defined stages of Alzheimer's entail, and it underscores the importance of considering alcohol use disorder as a risk factor for Alzheimer's."
Because the study was based on a small sample size for AUD, in the future, researchers plan to repeat their analysis using larger gene expression databases from individuals with AUD, which they expect to become available in the next year.
"We are eagerly awaiting the release of larger alcohol use datasets so that we can test the robustness of these findings and examine the commonalities between the two disorders with finer cell-type granularity," says Joshi.
"This is a global effort to unravel complex diseases at the single-cell level, which will lead to a better understanding of the molecular and cellular perturbations in individuals with Alzheimer's disease, alcohol use disorder, and their interactions."
In addition to Sanna and Joshi, the study, "Transcriptional Patterns in Stages of Alzheimer's Disease Are Cell-Type-Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans," was co-authored by Federico Manuel Giorgi of Scripps Research and the University of Bologna.
Author: Pietro Paolo Sanna
Source: Scripps Research Institute
Contact: Pietro Paolo Sanna - Scripps Research Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
"Transcriptional Patterns in Stages of Alzheimer's Disease Are Cell-Type-Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans" by Pietro Paolo Sanna et al. eNeuro
Abstract
Transcriptional Patterns in Stages of Alzheimer's Disease Are Cell-Type-Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans
Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD).
Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD).
We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type-specific gene expressions and pathway dysregulations that delineate AD stages.
Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type-specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others.
Evidence of inflammatory responses was seen in non-neuronal cells, particularly in intermediate and advanced AD.
We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support the role of excessive alcohol intake in AD progression.
Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD.
Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD.