Alcohol use disorder may exacerbate Alzheimer’s disease through shared genetic pathways

New research has uncovered a connection between Alzheimer’s disease and alcohol use disorder, suggesting that alcohol consumption might accelerate the progression of Alzheimer’s disease. The study, conducted by scientists at Scripps Research and published in eNeuro, found that both conditions share altered gene expression patterns in the brain, with similar disruptions in inflammatory and cell-death pathways. These findings offer a deeper understanding of the molecular mechanisms underlying Alzheimer’s disease and highlight alcohol use as a possible risk factor for its progression.

Alzheimer’s disease is the most common form of dementia, affecting nearly 7 million people in the United States, with numbers expected to double by 2060. Aging and genetic predisposition are well-established risk factors, but lifestyle choices such as alcohol use are also believed to influence the disease’s onset and severity. While heavy alcohol consumption is linked to cognitive decline and earlier onset of dementia, the specific molecular interactions between alcohol use disorder and Alzheimer’s disease remain poorly understood.

“While there are works that have studied early and late changes associated with Alzheimer’s disease, a systematic study of differential changes in the three clinically identified stages of the disease was lacking. Additionally, we were interested in evaluating excessive alcohol consumption as a risk factor for Alzheimer’s disease,” said study author Arpita Joshi, a staff scientist at The Scripps Research Institute.

The researchers conducted their study using a technique called single-cell transcriptomics, which analyzes gene expression in individual cells to uncover molecular changes with exceptional precision. They focused on the neocortex, a region of the brain critical for functions such as memory and reasoning, to investigate the transcriptional changes associated with Alzheimer’s disease and compare them to those seen in alcohol use disorder.

The study examined RNA sequencing data from brain samples of 75 individuals who were at different stages of Alzheimer’s disease progression—early, intermediate, and advanced—as well as 10 individuals without the disease. The data were obtained from a publicly available resource called the Seattle Alzheimer’s Disease Cell Atlas. These samples provided a comprehensive look at how gene expression varied across different cell types, including neurons, microglia (immune cells in the brain), and vascular cells, as Alzheimer’s disease progressed.

Free daily newsletter

To draw parallels with alcohol use disorder, the researchers analyzed a separate dataset that included RNA sequencing data from individuals with and without alcohol dependence. By comparing these two datasets, the researchers aimed to identify overlapping genetic pathways and molecular changes that might suggest common mechanisms underlying both conditions.

The team focused on specific biological processes, such as inflammation, cell signaling, and cell death pathways, which are known to be critical in neurodegenerative diseases. They also examined how gene expression changes were distributed among different brain cell types, allowing them to identify cell-specific patterns and insights.

The study revealed several key findings about the shared molecular features of Alzheimer’s disease and alcohol use disorder. One of the most significant discoveries was the overlap in transcriptional changes related to inflammation. Both conditions showed increased expression of inflammatory genes and pathways, particularly in microglia and vascular cells. These changes were associated with processes such as cytokine production, a hallmark of immune system activation, and disruption of the blood-brain barrier, which protects the brain from harmful substances.

Neuronal loss was another shared feature. Both conditions exhibited downregulation of genes involved in synaptic signaling, which is crucial for communication between neurons. This was particularly evident in advanced Alzheimer’s disease and in individuals with alcohol use disorder. Specific types of neurons, such as inhibitory neurons that regulate brain activity, showed significant gene expression changes, including disruptions in calcium signaling and intracellular processes.

The researchers also found evidence of vascular dysfunction in both conditions. Genes related to angiogenesis (the growth of new blood vessels) and extracellular matrix signaling, which are essential for maintaining blood vessel integrity, were negatively affected. These disruptions may play a role in the vascular damage observed in both Alzheimer’s disease and alcohol use disorder.

Interestingly, the study identified distinct patterns of gene expression across different stages of Alzheimer’s disease. Early stages were characterized by changes in genes involved in autophagy, a process by which cells clear out damaged components. In contrast, later stages showed heightened expression of neuroinflammatory markers and stress-related neuropeptides, as well as disruptions in synaptic signaling and pathways related to cell death.

The comparison with alcohol use disorder revealed that many of these changes were mirrored in individuals with alcohol dependence. This overlap suggests that alcohol use disorder may exacerbate or accelerate the progression of Alzheimer’s disease by affecting similar molecular mechanisms. The findings also provide a foundation for exploring alcohol use as a modifiable risk factor for Alzheimer’s disease, with potential implications for prevention and treatment strategies.

“Alcohol use disorder and Alzheimer’s disease have significant commonalities in terms of dysregulations that they cause, suggesting a potential exacerbating effect of alcohol use disorder on Alzheimer’s disease progression,” Joshi told PsyPost. “This research lays the foundation to better understand the molecular mechanisms behind Alzheimer’s progression and how alcohol can influence it.”

The research sheds light on shared molecular pathways between Alzheimer’s disease and alcohol use disorder. But as with all research, there are limitations. The dataset for alcohol use disorder was relatively small, which may affect the generalizability of the findings. Larger datasets with more diverse samples are needed to confirm these results and uncover additional molecular interactions.

“We found statistical significance for common perturbations only in the broad neuronal category of GABAergic/inhibitory neurons in intermediate and advanced Alzheimer’s disease,” Joshi noted. “Transcription factor analysis underlined many genes in both the diseases that are known to contribute to genetic disorders related to intellectual disabilities. The caveat is that the alcohol use disorder dataset is very small with only 3 AUD samples and 4 control samples. We need a larger dataset to do a more comprehensive study of alcohol use disorder in humans and then we can expect to derive insights at a finer granularity of cell-types and find further substantiation.”

Future research could also explore whether the shared genetic pathways translate to functional changes in brain activity and behavior. Understanding how alcohol use influences Alzheimer’s disease progression could lead to targeted interventions, such as drugs that modulate specific genetic pathways or lifestyle recommendations to mitigate risk.

“We are working on a new and larger alcohol use disorder dataset that will allow us to conduct a more detailed study and perform an even more comprehensive comparison with Alzheimer’s disease,” Joshi said. “We intend to delineate stages of alcohol use disorder and find out the types of Alzheimer’s-like orthogonal pathologies that it might contribute to. Our findings will stimulate further research in this area and may have implications for the development of novel or repurposing existing therapeutic approaches to tackle alcoholism.”

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 authored by Arpita Joshi, Federico Manuel Giorgi, and Pietro Paolo Sanna.