Alzheimer's: Excessive alcohol consumption may accelerate progression

• New research undertaken by scientists from Scripps Research and the University of Bologna reveals that combining genetic susceptibility with alcohol use disorder (AUD) may accelerate the advancement of Alzheimer’s disease.
• The research, conducted in mice, demonstrates that repeated episodes of alcohol intoxication in rodents with a genetic predisposition to Alzheimer’s lead to altered gene expression patterns, indicating a faster progression of the disease in their brains.
• These findings shed light on the molecular mechanisms underlying memory loss and may have broader implications for understanding and treating Alzheimer’s disease, regardless of alcohol consumption.

A new study, published in eNeuro reveals that mice exposed to regular high levels of alcohol exhibited cognitive decline approximately two months earlier than their typical progression when not exposed to alcohol.

Introducing ethanol to a genetic background prone to Alzheimer’s disease accelerates the onset of the condition by several months or even a few years.

While limited research has investigated the impact of alcohol on worsening Alzheimer’s disease, epidemiological studies have suggested that alcohol use disorder may increase the overall risk of developing dementia.

In order to investigate the impact of alcohol on Alzheimer’s disease, the researchers conducted an experiment where mice were exposed to repeated alcohol consumption over several months, reflecting the levels of alcohol exposure seen in individuals with alcohol use disorder.

They compared the behavior of control mice with mice that possessed three specific gene mutations associated with susceptibility to Alzheimer’s disease.

Alcohol and genetic risk may hasten progression

The results of the study revealed that the mice exposed to alcohol displayed a gradual decline in their ability to learn and remember spatial patterns, and they exhibited these cognitive impairments at an earlier age compared to the control group.

The researchers observed cognitive impairments in the mice subjected to alcohol treatment approximately 2 months before the typical timeframe when such impairments would manifest.

To understand the underlying mechanisms of alcohol use disorder, the researchers conducted a detailed analysis of gene expression in the brains of mice that were exposed to alcohol and those that were not.

They examined over 100,000 individual cells and compared their gene expression profiles.

The results indicated that alcohol exposure resulted in significant alterations in gene expression throughout the prefrontal cortex.

Specifically, the alcohol-exposed mice exhibited increased expression of genes associated with neuronal excitability, neurodegeneration, and inflammation.

These changes were not limited to neurons alone — supporting cells such as astrocytes, microglia, and endothelial cells also displayed altered gene expression patterns in response to alcohol exposure.

Previously it was believed that neurons were solely responsible for the responses related to Alzheimer’s disease, and only recently have these other cell types been acknowledged to have a role in the development of the disease.

Changes in gene expression and memory loss

The researchers compared the gene transcription profiles of the alcohol-exposed mice to unexposed mice at various ages and stages of Alzheimer’s disease but with the same genetic background.

They discovered that the gene transcription profiles of the alcohol-exposed mice were more similar to those of older mice experiencing more advanced cognitive decline rather than mice of their own age.

When the researchers compared the alcohol-exposed mice to the same type of mice at different stages of Alzheimer’s disease progression — including mice without any impairments and severely compromised mice — they observed that alcohol exposure shifted gene expression patterns towards those typically associated with advanced stages of the disease.

Dr. David Hunter, assistant professor of neurology with McGovern Medical School at UTHealth Houston, not involved in the study, highlighted the key findings to Medical News Today, explaining: “[T]his study exposed mice to alcohol. Some of the mice have human genes that cause Alzheimer’s. Other mice were normal controls. The mutant mice that were exposed to alcohol developed cognitive impairment earlier than those who were sober. Alcohol had no impact on the control mice.”

“The researchers also analyzed gene expression in the mice and found the mutant group with alcohol had some differences from the sober mutants,” he added.

“Animal models of Alzheimer’s disease are inherently challenging as mice do not naturally develop the disease. We have to give them multiple mutations that would be deadly to a human just to see any pathology,” Dr. Hunter further noted.

“This experiment proves that alcohol exposure altered the course of Alzheimer’s pathology in mice with multiple mutations, but that does not mean it would generalize to human alcoholics. (The vast majority of humans with Alzheimer’s do not have even one of these genes.)”
— Dr. David Hunter

Expert views on dementia and alcohol

Dr. Keith Vossel, professor of neurology and director of the Mary S. Easton Center for Research and Care at UCLA, also not involved in this research, told MNT that this research seems to complement previous findings about dementia and alcohol use.

“Excessive alcohol intake — over 21 units a week — has been associated with [a] higher risk of developing dementia,” he told us.

Nima Majlesi, director of Medical Toxicology at Staten Island University Hospital, also not part of the research, said the new study is “fascinating, and the more research that can be done on neurodegenerative diseases such as [Alzheimer’s disease], the more answers that can then be obtained for the betterment of everyone’s health.”

“There has never been any doubt that excessive alcohol use and recurrent intoxication [are] unhealthy in the medical community. There has occasionally been some doubt on whether a small amount of alcohol use daily can have health benefits. Even in patients not at risk for [Alzheimer’s disease], excessive alcohol use and recurrent intoxication [have] many detrimental effects on human health.”
— Dr. Nima Majlesi

However, Dr. Majlesi cautioned that “in this study, they exposed mice to ethanol vapors, which is not the typical route for human consumption.”

“We know that inhalational use of alcohol can lead to higher brain concentrations than the oral route. Metabolism of ethanol changes when exposure bypasses the [gastrointestinal] tract. This can lead to some variables that make the study slightly more difficult to interpret,” Dr. Majlesi said.

Alcohol a risk factor for all forms of dementia

Dr. Majlesi noted that “common sense tells us if we eat clean healthy foods daily, maintain a healthy weight, exercise daily, sleep well, and have little stress, we decrease our risk for a number of diseases.”

Dr. Hunter pointed out that “neurologists are well aware that chronic and excessive alcohol consumption is bad for the brain.”

“As this article mentions in its introduction, alcohol is also a statistical risk factor for all causes of dementia. It seems likely that it hastens the development of Alzheimer’s pathology even in sporadic patients. This article sheds some light on the mechanism of that link. The main implication for the public is that reducing alcohol intake is excellent advice to maintain a healthy brain.”
— Dr. David Hunter

“There is a disease called alcoholic dementia which is a neurodegenerative disease independent of Alzheimer. It presents with changes to executive function and visuospatial processing. Symptoms overlap with those of Alzheimer,” Dr. Hunter said.

Dr. Vossel agreed, adding that “there is also a rare form of dementia called Marchiafava-Bignami Disease associated with excessive alcohol intake and malnutrition.”

“More research on this topic is warranted. This study provides evidence that excessive alcohol intake can influence Alzheimer’s related genetic changes in the brain,” Dr. Vossel highlighted.

Dr. Vossel continued, “the control mice were not impaired by the excessive alcohol intake, but Alzheimer’s disease models were impaired.”

“Extrapolating to humans, it suggests that people living with or at high risk for Alzheimer’s might need to limit alcohol more than people who are not cognitively impaired.“

In conclusion, Dr. Vossel questioned whether the mice could be experiencing withdrawal symptoms and if this was more pronounced in the Alzheimer’s disease mouse models.

This interesting question could potentially be studied in a future research study.

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