By analyzing RNA from hundreds of thousands of individual brain cells, researchers have strengthened the notion that alcohol use disorder may speed up the progression of Alzheimer’s disease, which could lead to improved targeted treatments.
Currently, nearly 7 million people in the US have Alzheimer’s disease, and this figure is expected to double by the year 2060. While aging and genetic factors are the primary risks associated with Alzheimer’s, research indicates that lifestyle choices, including alcohol consumption, might also play a role in the onset and worsening of the disease.
Recently, scientists at Scripps Research discovered that both Alzheimer’s and alcohol use disorder (AUD) exhibit similar patterns of gene expression alteration in the brain. This supports the hypothesis that alcohol usage may enhance the progression of Alzheimer’s disease. The findings, published in eNeuro on September 19, 2024, could help guide future preventive measures and treatment approaches.
“Our research identified several unique genes and pathways that are disrupted in both Alzheimer’s disease and alcohol use, reinforcing the idea that alcohol use disorder can speed up the progression of Alzheimer’s by affecting some of the same molecular pathways involved in the disease,” comments senior author Pietro Paolo Sanna, MD, a professor in the Immunology and Microbiology Department at Scripps Research. “By exploring these disruptions in detail, we can better understand the causes of these diseases and pinpoint potential therapeutic targets.”
This study marks the first time researchers applied single-cell transcriptomics—a technique for analyzing gene expression at the individual cell level through RNA sequencing—to investigate the changes related to both Alzheimer’s disease and AUD across various types of human brain cells. This work builds on earlier findings from the Sanna lab that indicated excessive alcohol intake speeds up the progression of Alzheimer’s in genetically vulnerable mice.
To explore gene expression changes specific to certain cell types, the research team analyzed RNA sequencing information from hundreds of thousands of brain cells belonging to 75 patients at different stages of Alzheimer’s (early, intermediate, or advanced), and 10 patients without the disease. They then compared this data with existing RNA sequencing information from individuals with AUD.
The analysis demonstrated that both AUD and Alzheimer’s disease share common gene expression alterations in the brain, including increases in inflammatory genes and pathways, disruptions in cell signaling and cell death pathways, as well as modifications in blood vessel cells.
“What we’ve provided is a comparative analysis of two conditions that lead to cognitive decline,” remarks first author Arpita Joshi, PhD, a staff scientist in Sanna’s lab at Scripps Research. “This enhances our comprehension of Alzheimer’s disease across its three distinct clinical stages and highlights the significance of recognizing alcohol use disorder as a contributing risk factor for Alzheimer’s.”
Due to the limited sample size for AUD in this study, researchers intend to extend their analysis with larger gene expression datasets of individuals with AUD, which they anticipate will become available in the next year.
“We are looking forward to accessing larger alcohol use datasets to validate our findings and delve deeper into the common features of these two disorders with more precise cell-type analysis,” Joshi states. “This initiative is part of a worldwide effort to dissect complex diseases at the single-cell level, enhancing our insight into the molecular and cellular changes in individuals with Alzheimer’s disease, alcohol use disorder, and the interplay between the two.”
In addition to Sanna and Joshi, the article titled “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 from Scripps Research and the University of Bologna.
This study received funding from the National Institutes of Health (AA021667, AA028982, DA046170, DA046204, and DA053801).
