Summary: Repeated alcohol intoxication can speed up Alzheimer’s disease progression associated with a genetic predisposition.
The research demonstrated that mice exposed to consistent alcohol intoxication showed cognitive decline about two months earlier than typically expected. The findings indicate that alcohol use disorder (AUD) may advance Alzheimer’s disease by modifying gene expression, particularly in the brain’s prefrontal cortex.
Future studies plan to explore if alcohol consumption impacts the onset and progression of Alzheimer’s in individuals without genetic predisposition.
Epidemiological studies have suggested that Alcohol Use Disorder (AUD) may lead to a higher risk of developing dementia, including Alzheimer’s disease, but fewer studies have explored the direct impact of alcohol on Alzheimer’s progression.
This research used a model that exposed mice to repeated alcohol intoxication over several months, mimicking the levels of alcohol exposure seen in humans with AUD, providing a realistic scenario for understanding how chronic alcohol abuse may interact with Alzheimer’s.
The researchers also identified changes in gene expression not only in neurons, traditionally believed to be the primary cells responding to Alzheimer’s, but also in supporting cells such as astrocytes, microglia, and endothelial cells, highlighting a broader impact of alcohol on brain cell function and health.
Source: Scripps Research Institute
Alcohol use disorder (AUD) quickens the pace of Alzheimer’s disease progression when paired with genetic susceptibility. Scripps Research and University of Bologna scientists reported in the journal eNeuro on June 12, 2023, that repeated alcohol intoxication is associated with changes to gene expression indicative of disease progression in the brains of mice that are genetically predisposed to Alzheimer’s.
When repeatedly exposed to intoxicating amounts of alcohol, these mice showed signs of cognitive decline approximately two months sooner than they usually would.
“Adding ethanol to an Alzheimer’s genetic background pushes Alzheimer’s forward by a few months or a few years,” says co-lead author Federico Manuel Giorgi, PhD, a professor of Computational Genomics at the University of Bologna.
Though few studies have explored the potential for alcohol to exacerbate Alzheimer’s disease, epidemiological studies have hinted that AUD could lead to a higher risk of developing dementia in general.
To explore the potential for alcohol to affect Alzheimer’s disease, the researchers exposed mice to alcohol repeatedly over the course of several months in a model that mimics levels of alcohol exposure for people with AUD. They compared control mice to mice that carry three genes that make them susceptible to Alzheimer’s.
The team found that, compared to control mice, alcohol-exposed mice became progressively worse at learning and remembering spatial patterns, and they showed these signs of cognitive decline at an earlier age than usual.
“We started seeing cognitive impairments in the alcohol-treated mice approximately two months before they would normally develop these impairments,” says co-lead author Pietro Paolo Sanna, MD, a professor of Immunology and Microbiology at Scripps Research.
The researchers characterized and compared the gene expression of more than 100,000 individual cells from the brains of alcohol-exposed and unexposed mice to pinpoint exactly what was happening in these cells during AUD.
They found that alcohol exposure was associated with widespread changes in gene expression in the prefrontal cortex. Specifically, alcohol-exposed mice had higher expression of genes associated with neuronal excitability, neurodegeneration, and inflammation.
These changes occurred not only in neurons, but also in supporting cells such as astrocytes, microglia, and endothelial cells.
“This is interesting because it used to be thought that neurons were the ones carrying out all the responses associated with Alzheimer’s disease, and only recently have these cell types been recognized as having a role in Alzheimer’s pathogenesis,” says Giorgi.
When the researchers compared the gene transcription profiles of the alcohol-exposed mice to unexposed mice of different ages and stages of Alzheimer’s with the same genetic background, they found that the gene transcription profiles of the alcohol-exposed mice more closely resembled those of older mice with more severe cognitive decline than mice their own age.
“When we compared the alcohol-exposed mice to the same type of mice with early or late progression of the disease—so mice that are not yet impaired in any way and mice that are really compromised—we found that the effect of alcohol is to move gene expression towards the advanced disease,” says Sanna.
Understanding how gene expression changes in different populations of cells during Alzheimer’s is an important step toward understanding the molecular mechanisms behind memory loss and developing therapies.
The researchers speculate that the gene transcription pathways involved in Alzheimer’s progression with AUD may also help explain disease progression in the absence of alcohol consumption.
“The mechanisms of progression that this dataset will uncover may apply to Alzheimer’s in general, even without alcohol,” says Sanna. “Ultimately, this gene expression analysis will identify key regulatory genes that drive Alzheimer’s progression.”
Though this study focused on familial Alzheimer’s, in future the team plans to explore whether alcohol consumption also impacts the onset and progression of sporadic Alzheimer’s in people who are not genetically predisposed to the disease.
In addition to Sanna and Giorgi, authors of the study, “A history of repeated alcohol intoxication promotes cognitive impairment and gene expression signatures of disease progression in the 3xTg mouse model of Alzheimer’s disease,” include Amanda Roberts, Tomoya Kawamura, and Vez Repunte-Canonigo of Scripps Research; Chiara Cabrelle, Daniele Mercatelli of University of Bologna; and Nathan O’Connor of MBF Bioscience.
Funding: This work was supported by funding from the National Institutes of Health (AA021667, AA028982, AA006420, DA046170, and DA046204), the Italian Ministry of University and Research, the PNRR program, the HPC, and the Big Data and Quantum Computing project.
A history of repeated alcohol intoxication promotes cognitive impairment and gene expression signatures of disease progression in the 3xTg mouse model of Alzheimer’s disease
The impact of alcohol abuse on Alzheimer’s disease (AD) is poorly understood.
Here, we show that the onset of neurocognitive impairment in a mouse model of AD is hastened by repeated alcohol intoxication through exposure to alcohol vapor, and we provide a comprehensive gene expression dataset of the prefrontal cortex by the single-nucleus RNA sequencing of 113,242 cells.
We observed a broad dysregulation of gene expression that involves neuronal excitability, neurodegeneration, and inflammation, including interferon genes. Several genes previously associated with AD in humans by genome-wide association studies were differentially regulated in specific neuronal populations.
Gene expression patterns of AD mice with a history of alcohol intoxication were more similar to gene expression signatures of older AD mice with more advanced disease and cognitive impairment than those of younger AD mice with prodromic disease, suggesting that alcohol promotes transcriptional changes consistent with AD progression.
Our gene expression dataset at the single-cell level provides a unique resource for investigations of the molecular bases of the detrimental role of excessive alcohol intake in AD.