This study provides a detailed look at the relationship between Alzheimer’s disease (AD) and alcohol use disorder (AUD), investigating how excessive alcohol consumption may influence Alzheimer’s progression at the molecular and cellular level. By analyzing gene expression in individual brain cells, the team found shared disruptions in inflammation, cell signaling, and blood vessel function in both disorders. These findings highlight AUD as a potential risk factor for AD and may lead to new therapeutic targets.
Alzheimer’s disease is a form of dementia that progressively affects the brain, starting with mild memory loss and progressing to more severe damage that impairs communication and basic daily living skills.
An estimated 14 million people in the United States are expected to be living with Alzheimer’s by 2060. While factors such as age and genetics are known to be the main determinants of the disease, the study also explores the impact of alcohol consumption—a risk factor with complex effects.
In many cases, prolonged and excessive alcohol use, or even long-term abstinence, are risk factors for dementia, while regular and moderate consumption can have varying impacts.
One study in particular has linked alcohol use disorder to cases of early dementia, and research in animal models suggests that dependence can accelerate symptoms in mice predisposed to developing Alzheimer's.
The impact of alcohol on cellular processes is broad, involving important pathways for AD, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular alterations, all processes directly related to neurodegenerative diseases.
Alcohol also interferes with autophagy (the process by which cells eliminate damaged components), cerebral blood flow, and vascular integrity.
In this study, researchers at The Scripps Research Institute applied an advanced technology, single-cell transcriptomic analysis, to study the impact of alcohol and Alzheimer's at the level of gene expression in brain cells of people with Alzheimer's, covering early, intermediate, and advanced stages of the disease.
By analyzing the transcriptome (the complete set of RNA molecules in a cell), scientists were able to observe changes in the genetic activity of each brain cell. The team studied samples from 75 individuals with Alzheimer's and 10 people without the disease, isolating and analyzing gene expression in hundreds of thousands of individual brain cells.
For greater accuracy, they used the clinical staging of AD, which considers not only the presence of plaques characteristic of the disease but also the severity of other associated pathologies.
Table showing all genes identified in AD. Upregulated genes and Downregulated genes. Disease stages: Early, Intermediate, and Advanced
With this approach, scientists identified specific changes in gene expression throughout the progression of the disease, observing, for example, a progressive decrease in glutamatergic (excitatory) and GABAergic (inhibitory) neurons in different brain layers.
Within the GABAergic neurons, neurons that produce somatostatin (Sst) were particularly vulnerable early in the disease. In addition, they found significant reductions in subtypes of glutamatergic neurons, both in the superficial and deep layers of the brain.
The analyses also revealed that Alzheimer's and AUD share several altered pathways, such as neuroinflammation, phosphorylation, and calcium signaling. Genetic markers of AUD showed significant correlations with advanced AD, especially transcription factors involved in neuroinflammation and neuronal degeneration.
These findings suggest that accelerated progression of AD in patients with a history of heavy drinking may be associated with shared transcriptional mechanisms affecting how specific genes are expressed and influencing the disease.
In summary, the study provides new evidence that alcohol dependence may potentially exacerbate the progression of Alzheimer’s disease, suggesting that some of the biological processes involved in Alzheimer’s disease may also be triggered by heavy drinking.
This study provides a detailed analysis of the relationship between Alzheimer’s disease (AD) and alcohol use disorder (AUD), investigating how heavy drinking may influence Alzheimer’s disease progression at the molecular and cellular levels.
Distribution of the number of neurons in the corresponding cell types in each donor category in AD. a) All inhibitory neurons. b) All excitatory neurons. c) Sst. d) Sst Chodl. e) Vip. f) Sncg. g) Pvalb. h) L5/6 NP. i) L5 ET. j) L5 IT. k) L2/3 IT. l) L6 IT Car3.
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Transcriptional Patterns in Stages of Alzheimer's Disease Are Cell-Type–Specific and Partially Converge with the Effects of Alcohol Use Disorder in Humans
Arpita Joshi, Federico Manuel Giorgi and Pietro Paolo Sanna
eNeuro 19 September 2024, 11 (10) ENEURO.0118-24.2024
Abstract:
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 the 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.
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