In his 2022 docuseries, Limitless, actor Chris Hemsworth was told by Dr Peter Attia (author of Outlive) that, compared to the average population, he had an 8-10x higher risk of developing Alzheimer's disease in his lifetime. 

The cause? Chris carries two copies of the APOE E4 gene variant.

While not deterministic, the APOE E4 variant can significantly increase an individual’s risk of developing Alzheimer’s disease. In this blog, we’ll cover the function of the APOE gene, how the different APOE variants influence your Alzheimer’s risk, and which lifestyle interventions are most effective in mitigating this risk. 

What is Alzheimer’s disease? 

Alzheimer's is the most common form of dementia, contributing to up to 70% of cases^[1]. A progressive neurological condition associated with older age (65 years and older), symptoms of Alzheimer's include changes in memory, behaviour, perception, and emotions over time. 

The condition also often leads to physical challenges, including increased risk of falls and difficulty in eating food - with those in the condition’s later stages usually requiring support with daily tasks and selfcare. The average life expectancy following diagnosis is 8-10 years^[2]. 

How prevalent is Alzheimer's disease?

The World Health Organisation ranks dementia (of which Alzheimer's is a form) in the top five non-communicable causes of death globally^[3]. However, its effect on life expectancy is more pronounced in Western countries including the United Kingdom where ‘Alzheimer's disease and other dementias’ was listed as the top cause of death amongst British Women (all ages), and only followed ‘Ischaemic heart disease’ for British men (all ages)^[4]. 

Globally, 57 million people are currently living with dementia, with this number expected to exceed 130 million by 2050^[5]. 

What are the risk factors of Alzheimer's disease?

Your personal risk factors for developing Alzheimer's disease can be separated into two distinct categories: your lifestyle and your genetics. 

1. Lifestyle

Age

The most influential risk factor for Alzheimer's. The condition is typically associated with those aged 65 years or older, with an individual's risk doubling every 5 years after this age^[6]. 

Cardiovascular disease

Factors and conditions associated with cardiovascular disease including obesity, high blood pressure, high cholesterol, smoking, and excessive alcohol intake can all increase an individual's risk of Alzheimer's disease^[6]. 

Social isolation

The Alzheimer's Society reports that social isolation can increase an individual's risk of dementia by 60%, with lifelong single people more likely to develop the condition than those who are married^[7]. However, this interaction is complex, with debate as to whether social isolation is a risk factor or consequence of dementia. 

2. Genetics

Genetic factors that influence your Alzheimer's risk can be further divided between familial and risk genes. Familial genes are a direct cause of Alzheimer's, but are responsible for less than 1% of cases^[8]. Risk genes, of which APOE is the most common, influences your Alzheimer's risk but are not the singular cause of the condition. 

As reported by the Alzheimer's Society, nearly two thirds of people in the UK who develop the condition carry the APOE risk variant, demonstrating how influential genetics can be on an individual's risk^[8]. However, reassuringly for those who do carry the APOE risk variant, most people who carry this risk variant do not go on to develop the disease. 

What is the function of APOE?

The APOE gene provides the instructions for the production of apolipoprotein E (ApoE), a “lipid transporter responsible for delivering cholesterol and phospholipids throughout the body”^[9], including to the brain. As cholesterol and phospholipids are required for the regulation and function of neurons, ApoE plays a critical role in maintaining brain health. However, ApoE activity can also result in the formation of amyloid plaques between brain cells, which can lead to neurodegeneration and the onset of Alzheimer's. 

The rate at which these amyloid plaques form within brain tissue is influenced by which of the three ‘types’ (or isoform) you produce: APOE2, APOE3, or APOE4. These forms result from small changes within the base sequence of the APOE gene, but can have a large effect on the function of ApoE, with APOE4 associated with greater accumulation of plaques within brain tissue. 

Protective vs. risk APOE variants

There are three possible variants of the APOE gene. As we inherit a variant from each of our parents, each of us carry two variants, the combination of which dictates your ApoE isoform and therefore your genetic Alzheimer's risk: 

E2

The protective variant. Carriers of E2 show a lower risk of delayed onset cognitive decline and a significantly reduced risk of cardiovascular disease. Roughly 5% to 10% of people carry this variant^[10].

E3

The common variant, with the E3/E3 genotype found in 83% of the Euro-Mediterranean population^[11]. No increased risk, but also no protective effects.

E4

The increased risk variant. Resulting from “a combination of gain of toxic effects and loss of protective functions”^[9]. Approximately 15-25% of people carry one copy of the E4 variant, with 2-5% carrying two copies^[10]. Chris Hemsworth is a carrier of the E4/E4 genotype, placing him within the highest risk group genetically.

Actions to manage your Alzheimer's disease risk

While your APOE variants are set, you have control over your lifestyle factors. That’s why taking both into account when considering your overall Alzheimer's risk is critical. By making positive changes to your daily exercise, nutrition and social habits, you give yourself the best chance of maintaining cognitive function well into older age: 

1. Staying active

Incorporating both aerobic and resistance training into your weekly schedule is a proven way of reducing Alzheimer's disease risk, with people who exercise regularly 20% less likely to develop dementia than those who don't^[12]. Regular exercise helps to manage other long-term health conditions that drive Alzheimer's risk, including body fat levels and blood pressure. 

2. Reducing alcohol intake

Excessive alcohol consumption is linked to an increase in an individual’s dementia risk. Exceeding the NHS guidelines of 14 units per week can shrink parts of the brain involved in memory, while exceeding 28 units per week can lead to a sharp decline in thinking skills as you age^[13]. 

3. Being socially active

Staying in touch with family and friends through social activities can make you more resilient to the effects of Alzheimer's disease. This is enhanced further if the social activity is cognitively engaging, whether that’s playing an instrument, learning a language, exercising as a group, or volunteering.

Your FitnessGenes results report provides further, tailored recommendations to help you reduce your Alzheimer’s risk and support long-term cognitive health.

Conclusion

It’s important to remember that, while APOE E4 may increase your lifetime risk of developing Alzheimer's disease, most individuals who carry it will not go on to develop the disease. Likewise, not everyone with the protective APOE E2 variant is guaranteed to avoid it. This is because this particular genetic risk is not deterministic: in other words, it is not the sole and only factor that determines whether an individual develops Alzheimer's. 

However, understanding your relative genetic risk can help you to prioritise daily actions that will maintain your brain health into older age.

The influence of your lifestyle cannot be underestimated. Whichever variant of APOE you carry, neglecting your health - being sedentary, smoking, a lack of socialising - will significantly increase your risk of accelerated neurodegeneration. If, like Chris Hemsworth, you carry two copies of the E4 variant, there is plenty within your direct control that will help you to manage this risk.

As Chris said after discovering his personal APOE genotype: “it very quickly just became another wonderful motivation to make some changes and arm myself with all the tools to live a healthier, better life. Whatever I’m going to do now to benefit or protect [my brain health] will benefit every other aspect of my health and wellbeing.”^[14] 

Discover your personal APOE genetic risk

APOE is just one of the 180+ health and fitness reports that we deliver to our members at FitnessGenes. Each report identifies your individual risk and provides you with personal insights and recommendations to help you live healthier for longer. 

Purchase your home DNA analysis kit or DNA Data Upload today from fitnessgenes.com.

References

1. World Health Organisation, Dementia fact sheet
2. Alzheimer's Society, The later stage of dementia
3. World Health Organisation, The top 10 causes of death
4. World Health Organisation, Global health estimates: Leading causes of death‍
5. Alzheimer's Disease International, Wold Alzheimer's Report 2015
6. NHS, Causes Alzheimer's disease
7. Alzheimer's Society, Managing the risk of dementia, Social isolation
8. Alzheimer's Society, Risk factors for Alzheimer's Disease
9. Molecular Neurodegeneration, ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
10. National Institute on Aging, Alzheimer's Disease Genetics Fact Sheet
11. National Library of Medicine, The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity
12. Alzheimer's Society, Managing the risk of dementia, Physical activity
13. Alzheimer's Society, Managing the risk of dementia, Alcohol
14. Youtube, Chris Hemsworth talks learning about his risk of developing Alzheimer's disease