Could a mutation involved in alcohol metabolism contribute to Alzheimer’s disease?

Written by Sharon Salt, Editor

A mutation in ALDH2 – a key enzyme involved in alcohol metabolism – has been indicated to increase damage in cells obtained from individuals with Alzheimer’s disease (AD) and in mouse models. The study has been published in Acta Neuropathologica Communications.

This mutation in ALDH2 is associated with facial redness following alcohol consumption, which is a trait commonly referred to as ‘Asian glow’. The mutation occurs in approximately 8% of the world’s population and is more prevalent in the east-Asian population.

Although previous epidemiological studies carried out in this population have suggested there is an association between the mutation in ALDH2 and AD, other studies have not been able to draw this conclusion. To further explore this potential link, the authors of the present study observed cultures made from cells obtained from 20 individuals with AD.

One culture contained the ALDH2 mutation (referred to as ALDH2*2) and in this sample, the team noted that while the amount of ALDH2*2 protein matched the level of ALDH2 in normal cells, the mutated protein had only a fraction of the ability to breakdown acetaldehyde.

In addition to this, the ALDH2*2 cells were observed to have more free radicals and more 4-HNE (another toxic chemical usually processed by ALDH2) compared with normal cells. Daria Mochly-Rosen (Stanford University, CA, USA), who is the senior author of this study, stated that these levels of free radicals were restored to normal following the addition of Alda-1, which is a small molecule that ‘fixes’ ALDH2*2 by binding to the catalytic site and restoring the enzyme to a functional structure.

The addition of alcohol to ALDH2 or ALDH2*2 cells derived from individuals with AD also led to an increase in free radicals, with the greatest effect observed in the ALDH2*2 cells. Moreover, the addition of Alda-1 was reported to reverse these effects but not completely.

You might also like:

In mouse studies that were carried out, the investigators examined mice carrying ALDH2*2 that wee injected with alcohol every day for 11 weeks to simulate chronic alcohol use. Their results obtained were consistent with those observed in cell cultures – that is, when provided with alcohol, mice carrying the ALDH2*2 gene produced more free radicals than normal mice. The ALDH2*2 mice were also reported to have accumulated beta-amyloid protein fragments and activated tau protein more than their control counterparts. Alda-1 treatment also reduced the accumulation of both toxic proteins.

Furthermore, the ALDH2*2 mice exhibited an increase in neuroinflammatory signs following alcohol injection compared with normal mice, which was reduced with Alda-1 treatment.

The researchers subsequently prepared cell cultures from the brains of normal and ALDH2*2 mice and revealed that alcohol led to increased levels of free radicals and cell-death proteins not only in neurons, but astrocytes as well. Treatment with Alda-1 was noted to reduce the alcohol-induced changes in cell cultures.

Mochly-Rosen concluded that: “Our data suggests that alcohol and AD-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.”