Individuals, especially east Asians who carry a mutation in a key enzyme involved in alcohol metabolism, have an increased risk of developing Alzheimer’s disease as a consequence of regular alcohol consumption, according to recent research.
A recent study revealed that a mutation in a specific part of the aldehyde dehydrogenase 2 (ALDH2) gene, represented by the abbreviation ALDH2*2, may increase the risk of developing Alzheimer’s disease.
Interestingly, this mutation in ALDH2, which is much more common in east Asian countries where nearly half the population carries it, has been associated with facial redness following alcohol consumption, a phenomenon commonly referred to as “Asian glow.”
This manifestation is triggered by ALDH2’s inability to effectively detoxify the body from acetaldehyde, a toxic product of alcohol metabolism, leading to its accumulation.
Drinking alcohol on a regular basis been has show to be a risk factor for Alzheimer’s. Because ALDH2 is one of the key enzymes involved in the detoxification of acetaldehyde in the body, mutations that result in a deficiency in this enzyme further promote ethanol-mediated cellular damage.
Now, researchers at Stanford University School of Medicine studied the effects of ALDH2*2 in alcohol metabolism using skin cells from Alzheimer’s patients and mice genetically engineered to carry this same mutation.
The team observed increased concentrations of acetaldehyde in Alzheimer’s patient-derived skin cells — indicating the mutated enzyme could not efficiently degrade acetaldehyde. They also found greater oxidative stress and mitochondrial dysfunction, in comparison to healthy subjects. Importantly, ethanol exposure was found to exacerbate these dysfunctions.
Of note, oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, ultimately causing cellular damage (Mitochondria function as the cells’ powerhouses.)
The team then administered the equivalent of four-five drinks per day to mice with a mutated ALDH2 enzyme, and also to those with a normal form of the enzyme (controls) for 11 weeks.
However, because “mice metabolize alcohol much faster than humans, it comes to about two drinks a day,” lead author Amit Joshi, PhD, said in a press release.
Following chronic exposure to ethanol, ALDH2 deficient mice exhibited greater mitochondrial dysfunction (meaning less cell energy production), signs of neuroinflammation (known to contribute to the development of Alzheimer’s) and had an increase in cell-death proteins in neurons and in other brain cells called astrocytes. Astrocytes are cells that provide support to neurons and also may contribute to neuroinflammation.
Mutant mice exposed to ethanol also accumulated more beta-amyloid protein fragments and activated tau protein — molecular signatures for Alzheimer’s — than control mice. These animals also had compromised neuronal communication due to decreased synaptic health. (Synapses are junctions between two neurons that allow them to communicate.)
Importantly, a molecule that can activate ALDH2, known as Alda-1, was able to reduce ethanol-induced increase in amyloid-beta and tau protein, as well as neuroinflammation, in both mouse models and patient-derived cells.
“Our data suggest that alcohol and Alzheimer’s disease-prone genes may put humans at greater risk of Alzheimer’s onset and progression,” Daria Mochly-Rosen, PhD, said in a press release. “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,” said Mochly-Rosen, who is a professor of chemical and systems biology at Stanford University and the study’s senior author.
“These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to [Alzheimer’s] associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation,” researchers wrote.
“[I]n addition to reducing ethanol consumption (…), compounds that correct ALDH2*2 deficiency and activate non-mutant ALDH2, such as Alda-1, may provide a potential therapeutic avenue to slow down or reduce the pathology and burden associated with [Alzheimer’s] in the world’s aging population,” they concluded.
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