But now I want to pivot to discuss some of the research on alcohol and brain health. This is a fascinating area that there are some incredibly insightful studies that can inform us about the long-term effects of alcohol on the brain. There's one heavily referenced and incredibly informative study in this area that I want to lead with because it's been used as one of the main pieces of evidence as to why any amount of alcohol seems to be detrimental for the brain. The title of this study is Associations Between Alcohol Consumption and Gray and White Matter Volumes in the UK Biobank. The UK Biobank is a research database with health information from more than half a million European participants. And this study included data from about 36,678 individuals.

This study highlights the significant impact even moderate alcohol consumption can have on brain structure. Consuming just 1 to 2 units of alcohol daily, equivalent to roughly half to 1 standard drink in the US, is linked to reduced overall brain volume. This reduction includes both gray matter, which consists of neuronal cell bodies and is crucial for processing information, and white matter, which involves the connections between different brain regions. The way alcohol is measured in the study is critical to understanding its effects. In the UK, where the study was conducted, what's considered 2 units of alcohol is equivalent to 1 standard drink in the US, such as a can of beer or a glass of wine.

This means the detrimental effects on brain volume can occur at lower levels of alcohol intake than might be assumed by those using UK standards. Furthermore, the study supports existing evidence that alcohol contributes to cerebral volume loss, particularly affecting brain white matter. This loss impacts areas crucial for memory processing and visual spatial functions. In more severe cases, like those seen in individuals with alcohol use disorder, Heavy consumption leads to the loss of neurons in several critical brain regions, including the hypothalamus, cerebellum, hippocampus, and amygdala, areas involved in regulating emotions, memory, and spatial navigation.

Alcohol has profound negative effects on the brain, primarily through its impact on nutritional absorption, direct toxicity, and inflammatory processes. Let's break down these mechanisms. First, alcohol consumption can lead to a deficiency in thiamine. Or vitamin B1, which is essential for nerve function and brain health. This typically occurs in 2 ways. First, alcohol can impair the absorption of thiamine from the digestive tract. Second, it can inhibit the body's ability to utilize thiamine. This is because thiamine needs to be converted into its active form by an enzyme that alcohol inhibits. Additionally, this conversion process requires magnesium, another nutrient Often depleted by alcohol consumption.

The resultant thiamine deficiency can lead to decreased cellular defense against oxidative stress, contributing to brain damage. Some of this damage may be related to iron toxicity. Thiamine, also again known as vitamin B1, helps maintain the integrity of the blood-brain barrier. A thiamine deficiency could impair the blood-brain barrier function, allowing more iron to deposit into the brain. This is known as the brain iron overload and thiamine hypothesis. And though it is supported by some animal and neuroimaging studies, it is yet to be fully validated in humans. I will mention one study that observed an association between alcohol consumption and brain iron levels.

Consuming more than 7 units of alcohol per week was associated with higher iron levels and worse cognitive function among a cohort of more than 20,000 participants from the United Kingdom. I definitely think there is some support for the idea that iron in some way plays a role in alcohol-related cognitive decline. Acetaldehyde toxicity is another mechanism I want to talk about. When you drink alcohol, your body metabolizes it into acetaldehyde, a substance that is toxic to brain cells. This compound can damage DNA and proteins within brain cells, leading to cellular dysfunction and cell death. Neuroinflammation is another mechanism. So alcohol affects the gut-brain axis, as we discussed earlier. This is a direct communication pathway linking your GI tract to your brain.

Heavy drinking increases gut permeability. This is referred to as leaky gut. This can lead to the release of pro-inflammatory cytokines into the bloodstream. Once these cytokines are in the bloodstream, they cross the blood-brain barrier. They cause inflammation within the brain. Additionally, alcohol can increase glutamate, the excitatory neurotransmitter. It can activate the stress response system, further promoting brain inflammation. This inflammation is mediated by the activation of microglia and astrocytes. They're the brain's resident immune cells, which then release even more inflammatory mediators and cytokines resulting in this vicious cycle.

So the ongoing activation of these pathways by chronic alcohol consumption leads to sustained inflammation, which is detrimental for brain health. And it manifests as a significant neuronal loss, reductions in brain volume observed during even moderate drinking. All of this information doesn't paint the rosiest picture of alcohol and brain health. And based on this evidence, it would probably seem best to keep alcohol intake to below 1 drink per day. However, when we take a look at the epidemiological and clinical evidence on the relationship of alcohol to neurodegenerative diseases, the story does change a bit. Research shows that alcohol's impact on brain health and cognitive function is quite nuanced.

A number of studies have found that light-to-moderate alcohol consumption in middle to late adulthood is associated with a reduced risk of cognitive impairment and dementia, while heavy alcohol use and alcohol use disorder increase the risk for these diseases. There are lots of methodological differences among the studies in this area. So we'll do our best to try to make sense out of this evidence to try to provide some practical recommendations. Reduction associated with light-to-moderate drinking may be as high as 26 to 28% for dementia and Alzheimer's disease. But others suggest that the protective effects may be more modest.

In one analysis of 10 prospective studies, a lower risk for dementia was found to be zero— between 0 and 7.5 drinks per week, or just under 1 standard drink per day. But the lowest risk, a 10% reduction, occurred at 4 drinks per week. However, it's crucial to understand the dose-dependent response relationship alcohol has with cognitive health. So once consumption exceeds about 23 drinks per week, which equates to more than 2.5 drinks per day, the risk for dementia significantly increases. This suggests that while moderate drinking might offer some protective effects, Excessive alcohol use certainly outweighs these benefits and poses substantial risks. Unfortunately, some of the studies did not account for the sick quitter bias that we talked about earlier.

Remember that the sick quitter effect occurs when studies include both former drinkers and lifetime abstainers in the non-drinking group, which can artificially increase the risk for adverse health outcomes in the abstainers compared to light-to-moderate drinkers. This is especially important for brain health because the lasting effects of former heavy alcohol use on the brain may not be completely reversible after someone stops drinking. Although there is some evidence of a partial recovery of brain white matter in former heavy alcohol users after a period of abstinence. However, even studies that do account for the sick quitter effect have found a beneficial association between light-to-moderate drinking and the risk for dementia in middle-aged and older populations.

Whereas heavy drinking is often associated with a greater risk. So a study of adults between 35 and 55 years old found that abstinence from alcohol in midlife was associated with a 40% greater risk of dementia when compared to light-to-moderate alcohol consumption. This is of 1 to 14 units per week, an association that was still significant after taking former drinkers and abstainers into account. Drinking more than 14 units of alcohol per week was not associated with a greater risk of dementia, however. among adults consuming more than 14 units per week. Each 7-unit-per-week increase in alcohol consumption was associated with a 17% increase in dementia risk.

A protective effect of light-to-moderate drinking seemed to be mediated by cardiometabolic disease, so rates of which were higher in abstainers. We'll talk about the role of cardiometabolic health when we discuss the mechanisms that could explain the protective effects of alcohol on brain-related diseases. Another comprehensive analysis brings together data from over 15 international studies focusing exclusively on adults over the age of 60. This age specifically is crucial because it addresses a population at an increased risk for cognitive decline and dementia. The study's design cleverly accounts for what's known as the sick quitter effect. Again, this bias where individuals who have stopped drinking due to health issues might skew results if considered alongside lifelong nondrinkers.

So in this study, drinking categories were defined as follows: occasional drinkers consume about 1 drink per week, light-to-moderate drinkers consume up to 2 drinks per day, moderate-to-heavy drinkers have about 3 drinks per day, and heavy drinkers consume more than 3 drinks per day. The findings are quite revealing. Compared to those who abstain from drinking, occasional and light-to-moderate drinkers had a 22% lower risk of developing dementia. Those who drank moderately to heavily saw an even greater reduction with a 30% decreased risk. However, drinking more than 3 drinks daily did not show a statistically significant increase in dementia risk compared to abstainers.

Additionally, when isolating the data to only include current drinkers, the differences in dementia risk between light-to-moderate and moderate-to-heavy drinkers were no longer statistically significant. So this suggests that while moderate alcohol consumption might be associated with a reduced risk of dementia, moderate-to-heavy or excessive drinking does not have greater protective benefits and may plateau or even potentially lead to negative outcomes. So what can we take away from this study is that moderate alcohol consumption, particularly less than 2 drinks per day, might have a protective effect against dementia in older adults. However, escalating to higher levels of alcohol intake does not seem to provide additional benefits and could be risky.

I would say one noteworthy limitation of this study is the age of participants, which was 72 years, because none of the participants had been diagnosed with dementia at the time of the study. It's quite possible that these people had already a low general risk for dementia in the first place. So the results might not apply to the general population or people with a genetic predisposition to dementia. So speaking of genetic predisposition, now might be a good time to bring up apolipoprotein E3 and apolipoprotein E4. This is a topic that many people, including FoundMyFitness members who submitted questions for this podcast, may have concerns about. So there's a significant interaction between genetics and lifestyle factors that affects our brain health as we age.

One specific area of interest is the APOE4 allele. It's a genetic variation that is known to increase the risk of Alzheimer's disease and dementia. So apolipoprotein E, or APOE, is a gene that provides the instruction for our body to make apolipoprotein E, which combines lipids, cholesterol, and triglycerides to form lipoproteins. There are 3 common variations or alleles of the APOE gene. APOE2, APOE3, and APOE4. The APOE4 allele is associated with an increased risk of dementia and Alzheimer's disease and an earlier age of onset of these diseases in some populations. Around 15 to 25% of people have one copy of the APOE4 allele, and 2 to 5% carry 2 copies. Having one copy of this APOE4 allele elevates Alzheimer's risk around twofold compared to having no copies.

And having 2 copies of the APOE4 allele can increase the risk of Alzheimer's disease up to tenfold. If you want to determine whether or not you're a carrier of the APOE4 allele, you can do this by ordering a genetic test kit from one of the many available services such as 23andMe, AncestryDNA. And you can also run a free genetic report to determine your APOE status by uploading your genetic data to the FoundMyFitness website. Very few studies have investigated whether APOE4 modifies the association between alcohol and dementia or Alzheimer's disease risk. Some evidence suggests that the risk of dementia increases along with increasing alcohol consumption in people with one or more copies of the APOE4 allele, but not in people without the APOE4 allele.

So carriers of the APOE4 allele who consumed alcohol less than once a month still had 2.3 times greater risk of dementia than carriers who never drank, and carriers who drank several times per month had 3.6 times greater risk of Alzheimer's disease. So to put it another way, increasing alcohol consumption in midlife increases dementia risk only in adults carrying one or more copies of the APOE4 allele, at least when alcohol consumption stays below the threshold discussed earlier. Another study of older adults aged 59 to 71 years old found something similar for cognitive decline. Like previous studies, adults who reported consuming 2 or more alcoholic drinks per day had no copies of the APOE4 allele had a 30 to 74% lower risk of cognitive decline compared to non-drinkers.

On the other hand, for adults with one or more copies of the APOE4 allele, any alcohol was associated with a greater risk of cognitive decline, with 90% greater risk for 2 or less drinks per day, a 170% increased risk for 2 to 5 drinks per day, and a 730% increased risk For 5 or more drinks per day. Not all studies support a lower threshold for the negative effects of alcohol on dementia risk, such as one meta-analysis published in 2017, which actually found a protective effect of alcohol consumption up to 14 drinks per week among APOE4 carriers, while protection was only observed up to 7 drinks per week among non-carriers.

If we consider all these results, I think it's pretty clear that if you even have a single copy of the APOE4 allele, you should limit your drinking to occasional, but zero drinks appears to be the smartest choice to maximally reduce your risk of developing Alzheimer's disease or dementia. In any case, APOE4 carriers don't appear to experience the protective effect of light-to-moderate alcohol consumption that non-carriers have. Whereas most other epidemiological studies show that light-to-moderate drinking Is associated with a lower dementia risk in people without the APOE4 allele. Understanding how moderate alcohol consumption might positively or negatively impact dementia risk involves delving into the metabolic functions within the body.

Let's break down some of the key processes involved. First, one of the hallmark problems in Alzheimer's disease and other forms of dementia is impaired glucose metabolism in the brain. The brain's ability to utilize glucose effectively is crucial for maintaining cognitive functions. Alcohol interestingly might help improve the brain's glucose tolerance. This is potentially due to alcohol's ability to increase the presence of insulin-sensitive glucose transporters, which helps cells absorb glucose more effectively, thus supporting better brain function. Another critical aspect is how alcohol affects cardiovascular health, which is directly linked to brain health.

Moderate alcohol consumption has been shown to increase levels of HDL cholesterol, HDL plays a protective role in the cardiovascular system by helping remove other forms of cholesterol from your blood and preventing them from forming plaque in the arteries. Blood coagulation and platelet activity may also be involved. So Alzheimer's disease and dementia are also associated with abnormal platelet activity and other thrombotic factors that can affect blood flow. Alcohol can reduce platelet aggregation. Essentially, it can make platelets less sticky. And less likely to form clots. This reduction in coagulation and improvement in blood flow can be beneficial for brain health by ensuring that the brain receives adequate blood supply, which is essential for its function and maintenance.

There's one more mechanism I want to discuss, and that is alcohol's effect on the glymphatic system. The glymphatic system is our brain's highly organized system for cerebral spinal and interstitial fluid exchange, which is most active during sleep. It serves a few purposes. For one, it clears away waste products and metabolites from the intracellular space of the brain via lymphatic drainage vessels in the head and neck. These waste products, mostly proteins, protein aggregates, and metabolites, are then taken through circulation to the liver where they're degraded. 2 proteins of major importance here are beta-amyloid and tau, both of which are neurotoxic and have been implicated in the development of Alzheimer's disease.

Proper function of the glymphatic system ensures that these neurotoxic proteins don't accumulate. In mice, acute and chronic exposure for 30 days to a low dose of alcohol of 0.5 grams per kilogram body weight, corresponding to about 2 standard drinks per day for a human, actually improved glymphatic activity. Whereas intermediate and high doses corresponding to about 8 and 21 drinks per day for a human Impaired glymphatic activity. These results line up with all of the evidence that we've just discussed on the seeming benefits of light-to-moderate alcohol consumption on dementia and Alzheimer's disease and the detriments of heavier doses.

If any benefit indeed is due to alcohol, it might be via enhanced glymphatic drainage, but this probably requires that you avoid the negative impacts of alcohol on sleep because the glymphatic system is most active during this time. Sleep is when most of the brain's waste removal occurs. We'll talk more about how alcohol affects sleep very shortly. While the authors of this animal study caution that the results should not be used to make recommendations for alcohol consumption guidelines in humans, they do note that this may present a novel cellular and physiological mechanism contributing to the delay in onset of dementia in people with light alcohol intake. Namely through glymphatic clearance. So at the very least, it is an interesting mechanism that should be explored further.

Another interesting yet still debated idea in the realm of nutrition and brain health is the potential neuroprotective effects of compounds found in the nonalcoholic parts of alcoholic beverages like resveratrol found in red wine. Resveratrol is a polyphenol known for its antioxidant and anti-inflammatory properties. It has been studied for its ability to protect neurons by neutralizing free radicals, reducing inflammation, and enhancing neuronal energy metabolism. Some research has also suggested that resveratrol can improve cerebral blood flow and even aid in the clearance of beta-amyloid proteins, which are implicated in Alzheimer's disease. However, there's an important distinction to be made here between the effects of resveratrol itself and the effects of drinking red wine.

While resveratrol has been shown to have potential in laboratory studies, the actual amount of resveratrol in red wine is quite small, ranging from about 0.03 milligrams to 1 milligram per glass. To achieve the levels used in pharmacological studies, which are often between 50 to 500 milligrams, One would need to consume an impractical amount of red wine, literally thousands of glasses. Therefore, it's unlikely that the moderate consumption of red wine as part of a daily diet provides enough resveratrol to have a significant pharmacological effect on cognitive functions or neurodegenerative processes.

So while resveratrol is certainly a beneficial compound found in red wine, its concentrations in typical servings are too low to account for the observed health benefits associated with moderate wine consumption. This suggests that the other factors, perhaps even the alcohol itself, or a combination of other compounds and lifestyle factors associated with moderate wine drinkers, might be contributing to the protective effects noted in epidemiological studies on cognitive health and other diseases. So let's wrap up our discussion on the brain and hit a few takeaways from the research I've discussed. Alcohol's relationship with the brain is a tale of complexity and contradiction.

On the one hand, studies show that light-to-moderate alcohol consumption might reduce the risk of dementia in individuals without an APOE4 allele, which is a known genetic risk factor for Alzheimer's disease. This protective effect could be due to alcohol's influence on cardiovascular health, possibly improving blood flow to the brain and reducing inflammation, which are crucial factors in maintaining cognitive function. There is also some possibility that the glymphatic system activation could also play a protective role, But there's not enough evidence to support this last one yet. On the other hand, the same light-to-moderate drinking is associated with decreased brain volume.

To understand this, it's important to recognize that the brain structure and function are not always directionally correlated in a straightforward way. For instance, while reduced brain volume is generally viewed as negative, it does not necessarily translate to diminished cognitive function in this context. The key might lie in the body's resilience and compensatory mechanisms. The brain is highly adaptive and capable of compensating for certain types of structural changes. In the context of alcohol consumption, while there may be a general reduction in brain volume, the remaining neural networks might adapt in ways that maintain or even enhance cognitive functioning.

This could involve the strengthening of synaptic connections or improvements in neurochemical signaling, allowing the brain to operate efficiently despite structural reductions. However, this compensatory capacity is not uniformly distributed across all genetic profiles. Individuals with the APOE4 allele, which is the genetic variant linked to a higher risk for Alzheimer's disease, do not seem to exhibit the same level of neuroadaptability. For example, the APOE4 allele has been associated with reduced neurite outgrowth, which is crucial for forming new neural connections. This genetic difference means that APOE4 carriers may have less capacity to compensate for brain volume loss or other neural damages that occur with alcohol consumption.

So it is my opinion that to be on the safe side, limiting alcohol consumption to 1 to 2 drinks per week on social occasions, perhaps weekends, is probably not going to give you dementia per se. Finally, if you're a carrier of one or two of the APOE4 alleles, zero drinks per day is associated with the lowest risk for neurocognitive diseases. You might wanna limit your alcohol consumption to only social occasions, if ever.