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A mutation causing alcohol-related ‘Asian glow’ may have ties to Alzheimer’s disease

People with a mutation in an enzyme that breaks down alcohol may be at a higher risk for developing Alzheimer's disease, new research suggests.

If I drink even a few sips of alcohol, in minutes my face becomes tomato red. I, and another 560 million people, have a mutation in the aldehyde dehydrogenase 2 gene, ALDH2, that greatly reduces the activity of the enzyme coded by this gene. To put it plainly, we can't completely break down alcohol.

Instead, we build up a toxic intermediate, acetaldehyde, that causes flushing and inflammation. This mutation is particularly common in the East Asian population -- hence the term "Asian glow" for the flushing reaction.

Adding insult to injury, this mutation also may be putting us at risk for developing Alzheimer's disease if we drink alcohol, according to a new study published in Acta Neuropathologica Communications. The lead author is Amit Joshi, PhD, a postdoctoral scholar. The work is covered in a Stanford Medicine news release.

"Our data show that alcohol and Alzheimer's disease-prone genes may put humans at greater risk of Alzheimer's onset and progression," said Daria Mochly-Rosen, PhD, professor of chemical and systems biology and senior author of the study. "This is based on our current patient-derived cell studies and animal studies; future epidemiological study in humans will provide additional insight."

To understand the link between alcohol, ALDH2 and Alzheimer's disease, the researchers studied human cell cultures and mice that carry the human mutation causing Asian glow, ALDH2*2. To simulate chronic alcohol use, the research team exposed mice to alcohol over the course of 11 weeks.

The researchers observed that mice with the ALDH2*2 mutation produced more free radicals in their brains than normal mice in response to the alcohol treatment. ALDH2's job is normally to prevent the accumulation of these free radicals, Mochly-Rosen said.

"Once these aldehydes accumulate, the first organelles that they damage are the organelles that contain the enzyme, ALDH2, that is supposed to get rid of them: the mitochondria." Mitochondria are small machines in the cell that generate energy; when they are dysfunctional, they cause more free radicals and the cells ultimately die. This may play a part in the death of neurons in patients with Alzheimer's disease.

The mice with ALDH2*2 mutations also accumulated beta-amyloid protein fragments and activated tau protein more than normal mice when exposed to alcohol -- both of these changes are molecular signatures for Alzheimer's disease.

Mochly-Rosen and her team found that Alda-1, a small molecule that can "fix" ALDH2*2 and also activate normal ALDH2, reduced the accumulation of both of these toxic proteins. Mochly-Rosen and her colleagues discovered Alda-1 in 2008. Alda, which stands for aldehyde dehydrogenase activator, also happens to be Mochly-Rosen's mother's name: "She's 93 and very feisty. So far, Alda works well," she said.

The ALDH2*2 mice also showed a greater increase in neuroinflammatory signs following alcohol treatment compared to normal mice. Neuroinflammation, or inflammation in the brain, is normally caused by injury, infection and even the aging process, but recent studies have found that chronic neuroinflammation accelerates the progression of neurodegenerative diseases, such as Alzheimer's disease. Treatment with Alda-1 reduced the accumulation of these neuroinflammatory signs in mice.

These findings indicate that ALDH2 may have a previously uncharacterized role in the development and progression of Alzheimer's disease, Mochly-Rosen said. Next, researchers will need to conduct studies on larger human populations to see whether alcohol drinkers who have the ALDH2*2 mutation develop Alzheimer's disease at a higher-than-average rate, she said.

There have also been other studies demonstrating that ALDH2*2 mutation increases the risk of developing cancer in the esophagus. Because the enzyme ALDH2 is so important for human health, Che-Hong Chen, PhD, a senior research scientist, has organized a Stanford-Taiwan ALDH2 Deficiency Research (STAR) consortium. This group aims to promote research and public awareness about ALDH2 in East Asia, especially Taiwan, where nearly half the population has deficient ALDH2.

Photo by Patrick Fore

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