In the bustling world of Hollywood, Chris Hemsworth — best known for his role as Thor in the Marvel Cinematic Universe — has always been recognized for his commitment to wellness and health.
And yet, when he learned about his Apo-E4 status, it marked the beginning of a transformative journey that was as profound as any of his on-screen roles.
It was during the filming of National Geographic’s show Limitless that, as part of a thorough health checkup, Hemsworth underwent genetic testing to identify any risks or proclivities for diseases — a common procedure in the modern age.
A few weeks later, the results came in.
Hemsworth was a carrier of two copies of the gene ApoE4 allele, a variant of the apolipoprotein-E (Apo-E) gene that’s associated with an increased risk of late-onset Alzheimer’s disease. For someone who had always epitomized strength and vigor, the news hit him like a thunderbolt.
After taking some time off to assess, it seems that Hemsworth, ever the hero, decided not to view this genetic status as a dire prophecy, but instead as an opportunity to further refine his lifestyle and health habits.
Below, I’ve written a comprehensive review of Alzheimer’s, Apo-E4 epidemiology, mechanism, lifestyle factors, and treatment.
💡 A refresher on the prevalence of Alzheimer’s Disease
Alzheimer’s disease (AD) makes up 60–70% of the 50-million cases of Dementia worldwide, according to the World Health Organization, and this number is expected to increase with the aging population, reaching 82-million in 2030 and 152-million in 2050.
In the United States alone, Alzheimer’s disease is the sixth-most-common cause of death, with more than 5-million Americans living with the disease.
Apo-E4 and Alzheimer’s disease: absolute causality vs. correlation
Though genetics plays a crucial role in the development of Alzheimer’s, it’s not 100% causal.
More than a quarter of the US population carries an Apo-E4 allele (alleles are key ‘building blocks’ of the genes that form our chromosomes and, in turn, our DNA) — that’s the allele Chris Hemsworth discovered he carried.
But not everyone with this allele will develop Alzheimer’s. Other factors, like lifestyle and environment, also contribute to the disease’s onset.
Nevertheless, the correlation is there, and the presence of the Apo-E4 allele is no doubt one of the most major risk factors for late-onset Alzheimer’s Disease.
The Apolipoprotein-E gene, explained simply
The Apolipoprotein-E (Apo-E) gene is very important for lipid metabolism (how our body deals with fats).
It produces a protein that helps move cholesterol and other fats around.
There are three different versions of the Apo-E gene: E2, E3, and E4. Each version has a different impact on the risk of getting Alzheimer’s.
Apo-E2 is not very common — only about 8% of people around the world have it. It can actually help protect against Alzheimer’s, and is associated with lower levels of cholesterol in the blood and reduced risk of heart disease.
However, in rare situations, Apo-E2 can cause a condition called ‘type III hyperlipoproteinemia’, which can lead to problems like premature heart disease.
Apo-E3 is the most common variant of the allele. It’s found in about 77% of the population, and is generally considered neutral in its status as a risk factor of Alzheimer’s. This variant is linked to normal levels of cholesterol in the blood.
Apo-E4 — the variant we mentioned at the start of this article, which Chris Hemsworth discovered he carries — is found in approximately 15% of people globally.
It’s associated with an increased risk of developing Alzheimer’s — if someone has a copy of the Apo-E4 allele, they’re three times more likely to get the disease. If they have two copies of Apo-E4, the risk is 12 times higher.
This variant also leads to higher levels of cholesterol in the blood, which increases the risk of heart disease.
These differing variations of the Apo-E gene have effects beyond just Alzheimer’s disease; they can also impact how our bodies respond to different types of fats in our diet and exercise, and they can influence the risk factors contributing to other diseases, like cardiovascular disease and age-related macular degeneration.
Apo-E4, for example, has been known to worsen the effects of traumatic brain injury, and can increase the risk of cerebral amyloid angiopathy — a condition that can cause bleeding in the brain.
Again, it’s important to know that carrying a certain Apo-E gene doesn’t guarantee that you’ll develop Alzheimer’s. Some people with the Apo-E4 variant never do. The reverse is also true: people without Apo-E4 can get Alzheimer’s. Apo-E genes are just one of many factors affecting the likelihood of AD onset.
The role of Apo-E4 in the development of Alzheimer’s disease
The relationship between Apo-E4 and Alzheimer’s disease is quite complicated. It’s believed that Apo-E4 affects how a protein called amyloid-beta (Aβ) builds up in the brains of people with AD (read more about amyloid plaques in our May 2023 piece on the drug ‘Donanemab’).
Apo-E4 can attach to Aβ. By doing so, it’s harder to clear Aβ from the brain. And so, Aβ builds up. A 2013 study by Liu et al., which found that people carrying the Apo-E4 gene have higher levels of Aβ in their brains, supports this.
Apo-E4 may also play a part in causing neuroinflammation (inflammation in the brain) — another factor contributing to Alzheimer’s. It does this by making the immune cells in the brain — called ‘microglia’ — become more active.
Apo-E4 interacts with certain receptors on these cells, causing them to release molecules that cause inflammation. This inflammation can harm the brain cells and cause the kind of damage that’s a hallmark of AD.
Apo-E4 also increases the risk of other types of dementia, like Lewy body pathology and Parkinson’s disease dementia. It can also worsen cognitive problems experienced by people with vascular dementia. This is supported by a 1993 study by Corder et al.
Furthermore, Apo-E4 has been found to harm the protective barrier that keeps harmful substances in the blood from entering the brain (the blood-brain barrier). This damage is believed to allow toxic substances to build up in the brain, which exacerbates the development of Alzheimer’s.
Lastly, Apo-E4 has been linked to problems with synaptic plasticity, which is important for learning and memory. This impairment is thought to contribute to the cognitive deficits seen in AD patients. In a study by Dumanis et al. in 2009, it was found that Apo-E4 affects how well the connections between brain cells (neurons) — called synapses — work, leading to reduced synaptic plasticity.
The role of Apo-E4 in the development of Alzheimer’s disease
The relationship between Apo-E4 and Alzheimer’s disease is quite complicated. It’s believed that Apo-E4 affects how a protein called amyloid-beta (Aβ) builds up in the brains of people with AD (read more about amyloid plaques in our May 2023 piece on the drug ‘Donanemab’).
Apo-E4 can attach to Aβ. By doing so, it’s harder to clear Aβ from the brain. And so, Aβ builds up. A 2013 study by Liu et al., which found that people carrying the Apo-E4 gene have higher levels of Aβ in their brains, supports this.
Apo-E4 may also play a part in causing neuroinflammation (inflammation in the brain) — another factor contributing to Alzheimer’s. It does this by making the immune cells in the brain — called ‘microglia’ — become more active.
Apo-E4 interacts with certain receptors on these cells, causing them to release molecules that cause inflammation. This inflammation can harm the brain cells and cause the kind of damage that’s a hallmark of AD.
Apo-E4 also increases the risk of other types of dementia, like Lewy body pathology and Parkinson’s disease dementia. It can also worsen cognitive problems experienced by people with vascular dementia. This is supported by a 1993 study by Corder et al.
Furthermore, Apo-E4 has been found to harm the protective barrier that keeps harmful substances in the blood from entering the brain (the blood-brain barrier). This damage is believed to allow toxic substances to build up in the brain, which exacerbates the development of Alzheimer’s.
Lastly, Apo-E4 has been linked to problems with synaptic plasticity, which is important for learning and memory. This impairment is thought to contribute to the cognitive deficits seen in AD patients. In a study by Dumanis et al. in 2009, it was found that Apo-E4 affects how well the connections between brain cells (neurons) — called synapses — work, leading to reduced synaptic plasticity.
How lifestyle influences the relationship between Apo-E4 and Alzheimer’s
Lifestyle factors — particularly diet — can significantly influence the risk of Alzheimer’s in individuals carrying the Apo-E4 allele.
Western diets, characterized by high intake of saturated fats and sugars, have been associated with increased AD risk, particularly in Apo-E4 carriers.
This is thought to be due to the role of Apo-E in lipid metabolism (how our bodies process fats), with the Apo-E4 variant being less efficient at clearing dietary fats from the bloodstream.
Saturated fats are predominantly found in animal products such as meat and dairy, but also in certain types of oils. Diets high in saturated fat have been associated with a variety of health issues, including heart disease, obesity, certain types of cancer, and, more recently, dementia.
Conversely, diets rich in omega-3 fatty acids — such as the Mediterranean diet — may reduce AD risk, potentially by counteracting some of the detrimental effects of Apo-E4.
Mediterranean diets are rich in fruits, vegetables, whole grains, legumes, and olive oil, and it includes moderate amounts of fish and poultry.
This diet has been associated with a lower risk of heart disease and certain types of cancer, and research suggests that it may also have neuroprotective effects.
Other lifestyle factors like physical activity and cognitive engagement can also influence Alzheimer’s risk in Apo-E4 carriers. Regular physical activity has been shown to reduce the risk of the disease, likely by improving cardiovascular health and promoting neuroplasticity.
Cognitive engagement — reading, solving puzzles, and other mentally-stimulating activities — may also reduce Alzheimer’s risk by promoting cognitive reserve (put simply: your brain’s ability to improvise, and address tasks in complex ways).
The influence of lifestyle on Alzheimer’s risk in Apo-E4 carriers may be modulated by other genetic factors, too. The presence of other problematic alleles may amplify the detrimental effects of unhealthy lifestyle factors, while protective alleles may mitigate these effects. Therefore, personalized lifestyle interventions that take into account an individual’s genetic profile can be an effective strategy for reducing AD risk in APOE4 carriers.
Whilst living a healthier lifestyle can certainly reduce one’s chance of developing Alzheimer’s, it can’t completely eliminate the possibility. Therefore, individuals at high risk for AD — including anyone with the Apo-E4 variant — should also consider other preventive strategies, such as regular medical check-ups (which could help catch cognitive decline as early as possible).
The future of Apo-E4 and Alzheimer’s
Given Apo-E4’s significant role in the development of Alzheimer’s, it is a promising target for future treatments. One approach could be to develop drugs that can modify the function of the variant, making it behave more like the neutral Apo-E4 version. Treatments could also target the downstream effects of Apo-E4, such as Aβ accumulation or neuroinflammation.
Particular attention is being given to the production of structure correctors for Apo-E4, which aim to modify the protein’s structure to a less pathogenic (harmful) form. These correctors may be an important part of the future therapeutic landscape for Alzheimer’s.
To conclude, while Apo-E4 significantly increases the risk of Alzheimer’s, it does not guarantee its development.
Understanding the complex interplay between Apo-E4, lifestyle factors, and other genetic risk factors will be crucial for creating effective prevention and treatment strategies for AD.
As we continue to unravel the mysteries of Apo-E4 and its role in Alzheimer’s disease, it is essential to foster an environment of discussion and collaboration. The fight against Alzheimer’s is a collective effort, and every new piece of information brings us one step closer to a potential cure.
Discussing Apo-E4 and Alzheimer’s on The Brain Health Revolution Podcast
We talked more about the relationship between the Apo-E4 gene and the development of Alzheimer’s disease on our podcast, The Brain Health Revolution, as part of a live broadcast with our NEURO Academy community. Listen on Apple Podcasts, Spotify, or your favorite podcast app.
References
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Saddiki, H., Fayosse, A., Cognat, E., Sabia, S., Engelborghs, S., Wallon, D., … & Dumurgier, J. (2020). Age and the association between apolipoprotein E genotype and Alzheimer disease: a cerebrospinal fluid biomarker–based case–control study. PLoS Medicine, 17(8), e1003289.
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