What to Know About APOE4 Gene

Dec. 30, 2022 – In November, actor Chris Hemsworth announced that he would be taking a leave from acting to concentrate on his family and reassess his personal priorities. His decision was spurred by discovering a genetic vulnerability to Alzheimer’s disease while working onLimitless, a National Geographic docuseries focusing on ways to slow age-related declines. Hemsworth learned that he has two copies of the APOE4 gene (one from each of his parents), which is known to increase the risk of Alzheimer’s.

His revelation has brought renewed attention to the role of genes in Alzheimer’s disease. While there is cause for concern, there is no cause for alarm, says Howard Fillit, MD, co-founder and chief science officer  at the Alzheimer’s Drug Discovery Foundation. 

Yes, genetics can raise the risk of having Alzheimer’s, but genes aren’t the same as destiny, according to Fillit, who is also a clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at Mount Sinai School of Medicine in New York. The risk can be offset by things like healthy lifestyle behaviors.

What is the APOE4 Gene?

One of the important functions of the apolipoprotein E (APOE) protein, which is coded by the APOE genes, “is to carry and be involved with the metabolism of cholesterol and being involved with repairing neurons in the brain,” Fillit explains. “It also performs a lot of other functions, including binding to beta-amyloid, which is involved in the formation of plaques in the brain and neuronal injury, and is associated with Alzheimer’s disease.” 

The APOE4 gene codes for a mutated form of APOE and is one of the most significant genetic risk factors for getting Alzheimer’s disease. About 5% of the population has two APOE4 genes, and about 15% of the population carries one copy of the APOE4 gene, says Fillit. 

Having two copies increases a person’s risk of Alzheimer’s disease by about 15%, and people with two copies may start having symptoms 10 years earlier than the average person. But that doesn’t mean that everyone with two copies of the gene will definitely go on to get Alzheimer’s.

Genes Can Be ‘Turned On’ or ‘Turned Off’ 

Although one’s genetics can’t be changed, your risk can be reduced, even if you have the APOE4 gene, Fillit notes. 

The Lancet Commission on Dementia Prevention, Intervention, and Care identified 12 changeable risk factors for the development of Alzheimer’s disease: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, traumatic brain injury, and air pollution. Taken together, these factors account for around 40% of worldwide dementias. 

Research supports the role of a healthy lifestyle in improving thinking skills and memory in older adults with the APOE4 gene. Fillit points to the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which was a clinical trial done in six centers across Finland. It found that a healthy diet and management of vascular risk factors, as well as physical, cognitive, and social activities, helped slow cognitive decline, even in this high-risk population. 

Uma Naidoo, MD, director of nutritional and lifestyle psychiatry at Massachusetts General Hospital in Boston, says that with the exception of certain congenital conditions, “our genes may influence our risk of developing a certain condition,” but those genes can be “turned on” or “turned off,” depending on things like your environment, lifestyle, and age. 

Brain-Healthy Nutrition

Naidoo, who is also a faculty member at Harvard Medical School, stresses that a healthy diet can help stave off cognitive decline and dementia. 

“As a nutritional psychiatrist, my work is focused on the use of healthy whole foods and nutrients to help improve mental well-being in the context of a healthy lifestyle, using a holistic and integrated approach,” she says. 

Optimizing our diet “can support a healthier mood, healthier brain, and reduce the inflammation associated with the neurodegeneration that underlies Alzheimer’s disease,” continues Naidoo, a professional chef, nutritional biologist, and author of the book This Is Your Brain on Food

Naidoo highlights the relationship between gut and memory. 

“While there are lots of factors at play, it’s vital to understand that many of the chemicals that control the brain and body are regulated by the gut, and the composition of gut bacteria is actually drastically different in patients with neurological diseases such as Alzheimer’s.”

A nutrient-dense, anti-inflammatory diet that includes foods rich in probiotics can improve the gut microbiome – the bacteria in the gut – “in a way that resists the development and progression of Alzheimer’s,” Naidoo says.

Recent research points to the negative impact of ultra-processed food on memory and dementia. The World Health Organization’s recommendations for lifestyle changes to prevent cognitive decline and dementia include a healthy diet rich in fruits, vegetables, legumes, nuts, and whole grains, with less than 30% of total calories coming from fats, and less than 5 grams of salt. In particular, the WHO recommends a Mediterranean-like diet, limiting red meat and full-fat dairy, and consuming only low to moderate amounts of alcohol.

Get More Exercise

The WHO also recommends physical activity to reduce the risk of cognitive decline. 

“Both aerobic and strength training exercises have been linked to improved cognition and reduced cognitive decline in older adults,” says Belinda Brown, PhD, deputy director of the Center for Healthy Ageing at Murdoch University in Perth, Australia. 

“Research also shows aerobic exercise can increase the volume of the brain, and there is emerging evidence that yoga and tai chi may be protective of the brain in later life, likely in different ways than aerobic exercise,” says Brown, whose research focuses on understanding the role of lifestyle – particularly exercise – in maintaining a healthy aging brain and preventing cognitive decline and dementia. “Research suggests that being physically active may even counteract negative effects of having APOE4.” 

“Exercise” includes a range of physical activities, including sports and planned exercises, walking, cycling, and even household chores. The Alzheimer’s Association offers recommendations for staying safe and physically active.

Sleep’s ‘Sweet Spot’ 

Much attention has been focused on nutrition and exercise in preventing or slowing cognitive decline and dementia, but “as a society, we’re finally waking up to the importance of sleep,” according to Rebecca Robbins, PhD, a faculty member at Harvard Medical School in Boston. 

“One of my favorite areas of sleep science is uncovering how important sleep is from the standpoint of our brain,” she says. “When we get a healthy amount of sleep and consolidated sleep duration, we wake up and not only feel better the next day, but the sleep might also play a critical role in moving dangerous toxic particles that build up in our brains, which are the byproducts of learning new information.”

Studies have shown that during sleep, there is a 60% increase in clearance of those toxic particles, compared to wakefulness. These particles add to the buildup of beta-amyloid, explains Robbins, who is also the co-author of the book Sleep for Success.

There is a “U-shaped relationship” between sleep and several adverse outcomes, with too much and too little sleep being problems, she says. 

“The best health and well-being are seen in people whose sleep duration is in the ‘sweet spot’ of 7 to 9 hours per night. All of this points to the hypothesis that sleep plays a pivotal role and is a really important lifestyle factor to focus on when optimizing health and performance.” 

Other Lifestyle Factors

Reducing your risk for Alzheimer’s disease includes addressing as many other risk factors as possible:

  • Quit smoking. 
  • Reduce stress and address depression; mind-body approaches and psychotherapy might help.
  • Reduce exposure to air pollution.
  • Work with your health care provider to manage conditions like diabetes, high blood pressure, high cholesterol, hearing impairment, and obesity.
  • Increase social and recreational activities, and keep your brain active.

Who Should Receive Genetic Testing?

Fillit doesn’t advise routine genetic testing for Alzheimer’s disease. 

“I’d recommend it in patients with a strong family history of Alzheimer’s or if a younger person – let’s say someone in their 60s or younger – is experiencing memory loss or other symptoms of dementia.” 

Being tested is a very personal decision, he notes. 

“Some people want to know their risk, while others don’t. Some people might want to know if their children are at risk,” he says. 

Having the information can help if it’s a motivation to make lifestyle changes. 

“The value of getting tested, especially in families with generational Alzheimer’s disease in parents, siblings, or grandparents, would be to ensure compliance with prevention programs, avoiding risk factors, and getting advanced care planning, such as advanced health care directives, and wills in place,” says Fillit.

More resources on lifestyle factors for improving brain health and preventing cognitive decline, and on the role of genetics in Alzheimer’s risk, are found below.