Research suggests contributory role of 'Asian glow' mutation and alcohol to Alzheimer’s

A new study from Stanford, published on December 12 in the journal Acta Neuropathologica Communications, suggests that an important enzyme that helps break down alcohol in the body is defective in patients with Alzheimer’s disease (AD).  Understanding its relationship with alcohol and with genes that predispose to AD could help avert the latter in humans at risk.

Image Credit: Sugar Lime studio / Shutterstock
Image Credit: Sugar Lime studio / Shutterstock

The “Asian glow” mutation

This specific mutation in the enzyme called aldehyde dehydrogenase 2, or ALDH2, causes facial flushing after an alcoholic drink. More common in East Asians, where it affects almost half the population, it is called the “Asian glow” mutation. It causes severe reduction of enzyme activity, causing a toxic intermediate alcohol metabolite called acetaldehyde to accumulate. This in turn results in facial flushing, and an inflammatory response. The underlying mutation is found in about 8% of the world’s population, or about 560 million people.

Researcher Daria Mochly-Rosen says that it is important to know more about how AD-linked genes are related to alcohol, since this association could be inadvertently allowing millions of people to damage their long-term health through regular drinking. According to experiments on cells from such patients and from mice, she says, “Our data suggest that alcohol and Alzheimer's disease-prone genes may put humans at greater risk of Alzheimer's onset and progression. This is based on our patient-derived cell studies and our animal studies, so an epidemiological study in humans should be carried out in the future.”

The study- stage 1

Older epidemiological studies in East Asians have pointed to a link between this mutation and AD, but results have been mixed. To try to resolve this confusion, the current study looked at cell cultures they had grown from cells retrieved from 20 AD patients. Among these, the cells in one culture had the ALDH2 mutation which is commonly denoted by ALDH2*2.

When the researchers assayed, or measured, the amount of the ALDH2*2 protein in this cell culture, it was similar to that of ALDH2 protein in the other cultures. However, its activity was minute compared to that of the normal enzyme when it came to degrading acetaldehyde.

As a result of impaired enzymatic processes, there were significantly more free radicals within the ALDH2*2 cells as well as higher amounts of 4-HNE, which is a second toxic chemical that is also a substrate of this enzyme.

Free radicals and ALDH2

Free radicals are signals of cellular stress, as occurs when the body is chronically inflamed, has fever, or is exposed to high levels of pollution. They react with normal cell constituents to form aldehyde molecules, which are also toxic. ALDH2 in the normal cell reacts with these aldehydes to break them down into nontoxic forms.

However, with the defective enzyme, acetaldehyde accumulates, leading primarily to damage to the mitochondria that houses the ALDH2 enzyme. This further reduces enzyme activity. The outcome is eventual reduction of mitochondrial activity, increased release of free radicals by the mitochondria due to damage, and, in patients with AD, to neuronal death.

Stage 2 – Alda-1 to the rescue

The experiment went on to assess what would happen if another small molecule called Alda-1 was added to the cell. Alda-1 restores normal enzyme activity by a simple fix, binding to the site that promotes the actual catalytic activity of the enzyme so that it becomes a fully functional enzyme again. As a result, the level of free radicals dropped drastically to come back to normal.

Alda-1 was found to have this capacity to restore ALDH2*2 to normal back in 2008 by Mochly-Rosen and her research team. In addition to this fixing role, it also activates the normal enzyme, which could give it a wider spectrum of usefulness.

At present, Alda-1 and other similar molecules are being tested in clinical trials for their capacity to treat a number of health conditions. The researchers discovered that while free radical levels rise in cells with either ALDH2 or ALDH2*2, when alcohol is added, the rise is significantly greater in the latter. The addition of Alda-1 led to a marked but still partial restoration of function of the enzyme.

The scientists conclude that drinking alcohol leads to damage to cells that are protected by the ALDH2 enzyme, and that with patients who have genes that are linked to AD, this damage is more serious. This suggests that patients with genetic AD risk should not drink alcohol at all.

Stage 3 – rescuing mice

To confirm the role of alcohol in ALDH2 activity, the experiment proceeded with mice that have the defective form of the gene. Alcohol was injected into these mice every day for 11 weeks, to mimic the pathological changes of chronic alcoholism. The dose was 1g/kg/day – equivalent to a human consuming about 2 drinks a day, because mice normally process alcohol at a much faster rate than humans do.

The researchers found that free radical levels zoomed up in mice with the mutation compared to normal mice, when exposed to alcohol. Not only so, beta-amyloid accumulation and increased activated tau protein levels were also observed – changes that are characteristic of AD at molecular level. When the mice were treated with Alda-1, the amounts of both these molecules showed a significant reduction.

Mutant mice also showed more signs of neuroinflammation when injected with alcohol than normal mice. Inflammation in the nervous system is typically due to injury, infection or aging. However, it also speeds up the development of degenerative disease in the nervous system, of which AD is a classic example. When these mice were treated with Alda-1, the levels of these proteins also dropped.

Alcohol and neuroinflammation

In a final experimental setup, the researchers grew cells take from the brains of normal mice as well as those with the mutation in culture. The result was that alcohol exposure led to higher levels of free radicals and other toxic protein products within both neurons and astrocytes, that support cells of the central nervous system that maintain normal function of nerve cells but also take part in inflammation within the nervous system. Alda-1 treatment partially reversed these changes in cell cultures as well, they found.

Future directions

The study found a novel role for alcohol and the ALDH2 gene in AD, working with cells in culture and in mice. The research must be validated in larger human epidemiological studies. This will show if the presence of the ALDH2*2 mutation in alcohol drinkers drives the development of AD at a higher rate. Such studies will determine if lowering the level of alcohol and treatment with Alda-1 and other similar molecules can prevent or reduce the progression of AD and bring down the global burden of this disease among the world’s elderly people. If so, such drugs could help reduce AD risk.

ALDH2*2 could also increase the risk of esophageal cancer, according to other research. This has prompted the Mochly-Rosen laboratory to set up the Stanford-Taiwan ALDH2 Deficiency Research Consortium, or STAR, to increase the level of awareness about this mutation among East Asian populations.

Journal reference:

Joshi, A.U., Van Wassenhove, L.D., Logas, K.R. et al. Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology. acta neuropathol commun 7, 190 (2019) doi:10.1186/s40478-019-0839-7, https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0839-7

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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