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Is Alcohol Destroying Your Brain? Check Your Genes

Everybody should know by now that chronic excessive alcohol use leads to a plethora of health problems, including but not limited to, liver disease, pancreatitis, various cancers, gastrointestinal issues, decreased immune system function, malnutrition, osteoporosis, and of course brain damage, or “drain bamage”, as it’s cheekily referred to as. (1–8)

The real question is: can moderate, or even light alcohol consumption be detrimental to brain health? Until rather recently, there have been mixed findings, with some research finding positive effects or neutral effects on brain function and other studies reporting negative changes in cognitive abilities. When genetic variations are controlled for, the answer becomes more clear, and that is — it depends on your genes. (9–11)

In particular, two genes are especially important in determining your susceptiblity to alcohol-related cognitive decline. They are the APOE gene and the SOD2 gene. The “bad guy” versions of these genes, if you will, are the E4 allele for the APOE gene and the G/G (or C/C) mutation for the SOD2 gene.

The APOE Gene

The APOE gene is involved in the transport of cholesterol across tissues; however, recent evidence reveals it is far more than a single-function gene. Besides regulating cholesterol homeostasis, the APOE gene has antioxidant and anti-inflammatory properties that help protect against neuroinflammation and neurotoxicity as well as maintain neurogenesis (i.e., the creation of new brain cells). (12–13)

There are three variants of the gene: E2, E3, and E4. Since we inherit one version of the gene from each parent, we possess genotypes such as E2/E3, E3/E3, E3/E4, and so on. The E4 allele is the least efficient in these antioxidant and inflammatory abilities. (14) It also negatively affects cholesterol regulation, and is consistently associated with poorer cholesterol profiles (e.g., lower HDL/LDL ratios). (17) Inheriting just one copy of the E4 allele increases the risk of Alzheimer’s by 2 to 3-fold, while possessing two copies increase the risk by around 14-fold. (15)

The neurotoxicity of alcohol is exacerbated by the E4 allele through increased generation of oxidative stress and neuronal death. (16) Furthermore, alcohol consumption raises LDL levels (bad cholesterol) in E4 carriers — who are already susceptible to an altered lipid profile — which in turn elevates the risk of vascular dementia. (18–19) Put another way, the threshold by which alcohol exerts deleterious effects on brain health is lowered for E4 carriers. Whereas light alcohol consumption (e.g., 1–6 drinks per week) and abstinence are equally protective against cognitive decline in non-carriers, light alcohol consumption is associated with a greater decline in memory and learning in older age in E4 carriers. (20–21) Other studies have found that even infrequent drinking (e.g, less than once a month) predisposes E4 carriers to dementia and Alzheimer’s disease. (22–23) It is very possible that “infrequent drinkers” in these studies included binge drinkers as this style of infrequent yet binge-type drinking is common in the country (Finland) where these studies took place. Binge drinking has been shown to result in DNA damage even in young college-aged drinkers with only 4–5 years of drinking history, so it is not so much a stretch to reasonably assume that a lifestyle of binge drinking, albeit infrequent, will hasten the decline of brain function in vulnerable E4 carriers, especially considering that the E4 isoform has a decreased capacity for neuronal repair. (13) When it comes to heavy drinking, those with E4 alleles who also frequently smoke are diagnosed with AD on average of 10 years earlier than E4 non-carriers who do not drink or smoke. (24) With increasing frequency of alcohol, the risks for later brain damage are magnified among E4 carriers. Safe(er) E4 carriers are abstinent E4 carriers. (22–23)

The SOD2 Gene

SOD2, short for manganese superoxide dismutase, is an enzyme that acts as our very own naturally-occurring antioxidant that combats mitochondrial oxidative stress. A variation of its amino acid sequence is caused by a missense mutation where an amino acid within the chain called “valine” is substituted with “alanine”, causing an adverse change in the function of the enzyme due to the resultant structure alteration. Those who are valine carriers possess the allele A (or T) whereas those who present with the alanine substitution have the G (or C) allele. The G/C allele is associated with lower SOD2 activity, which means mitochondrial antioxidant defense is compromised. Unlike the APOE gene, one copy of the inferior alanine-containing SOD2 enzyme does not cause a major change in the enzyme’s activity, but having a homogyzous mutation for SOD2 (e.g., inheriting both copies of the G/C allele) is associated with negative changes in the brain independent of alcohol usage. Healthy non-smoking individuals who are homozygous for the G/C allele (GG or CC carriers) have higher levels of DNA damage than those without the alanine allele. This increase in DNA damage is also evident in heterozygous carriers (e.g., one copy of the G/C allele and one copy of the A/T allele) as well, albeit to a lesser extent. (25) Exaggerated age-related changes such as greater deterioration in white matter connectivity in multiple areas of the brain have also been found in GG (CC) carriers in comparison to GT or TT carriers, which is related to various parts of cognition such as executive function, processing speed, and memory. (26) In addition, the G © allele has been over-represented in Alzheimer’s disease. (27)

When alcohol is involved, those who are homozygous for the mutation (carrying 2 copies of the bad allele — GG or CC) are found to have exaggerated gray matter loss compared to heterozygous carriers (G/A or C/T) and especially compared to those with both copies of the beneficial allele (AA or TT). It must be noted that this association was found among the chronic light to moderate-heavy drinkers, meaning that the negative brain changes manifest at the low end of the drinking range. There was no difference in adverse brain changes in the very heavy drinkers as even the higher antioxidant activity allele is not protective at that stage. (28)

Are You an E4 Carrier AND/OR Did You Inherit Both Faulty Copies of the SOD2 Gene? Get Tested

Before deciding to take the necessary precautions below or to carry on drinking ostensibly harmless amounts of alcohol with a relatively healthy lifestyle under the assumption that you did not inherit either of these not-so-uncommon genes, it would be wise to get tested.

From there, within your account, you can “Browse Raw Data” by typing in the SNP (basically the marker for genetic variation) in question and see which two alleles you’ve inherited. The SNPs you want to look at for the APOE gene are rs429358 and rs7412. If you are an E4 carrier, you will read C/T for rs429358 and either C/T or C/C for rs7412. If you are carrying both E4 alleles, you will be C/C for rs429358 and rs7412.

The SOD2 SNP is rs4880. Those homozygous for the low-activity allele will see G/G whereas those homozygous or carrying one high-activity allele will read AA or A/G, respectively.

How To Help Protect Yourself

If you are an E4 carrier, a homozgyous carrier for the inferior allele for SOD2, or both, you may wish to implement special lifestyle modifications to mitigate your risk/s for suboptimal brain aging. Without alcohol in the equation, these gene variants, especially E4, increase the risk for accelerated cognitive decline. No matter what, those affected should consume a healthy diet rich in antioxidants and engage in frequent physical activity.

The best advice would be to abstain from alcohol entirely and seek pleasure from other activities. After all, alcohol is a carcinogen, despite the fact that it is socially acceptable in society while cigarette smoking is demonized. E4 carriers might want to substitute their alcoholic drinking for high-antioxidant green or black tea, which appears to reverse the risk of cognitive decline in this vulnerable subgroup. (29) Realistically, not everyone wants to forego alcohol drinking entirely. If you choose to drink, it would be smart to drink sparingly and to choose alcoholic beverages with high antioxidant activity to help balance out the negative effects of alcohol, such as red wine, although higher consumption is still harmful. (30)

E4 carriers who wish to drink should make sure to increase their intake of low-mercury seafood (and/or supplement with fish oil) and decrease their saturated fat intake as a lifetime protective measure. (31–32) On top of that, supplementation with an active B complex (especially with folate/5-Methyltetrahydrofolate), acetyl-L-carnitine (ALCAR), alpha lipoic acid (ALA), and S‐adenosyl methionine (SAMe) is recommended. (33–34) Resveratrol is also helpful in improving APOE expression. (35)

SOD2 low-activity allele carriers can significantly decrease their enhanced DNA damage with combined typical dietary antioxidants including selenium, vitamin A, vitamin C, and vitamin E. (25) For additional protection that is needed with alcohol consumption, resveratrol can help amplify SOD2 expression. (35–36) On the more expensive end, one may invest in Tempol, a SOD2 mimetic drug, and achieve similar SOD2 antioxidant activity that is achieved by inheriting two copies of the superior allele. SOD supplements are not recommended for this specific genetic susceptibility as they target the gene SOD1, not SOD2.

References:

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