ApoE4 2022 Update – What Experts Say About Nutrition

September 26, 2022

Whether you’re concerned about your Alzheimer’s risk due to family history, ApoE4 status, or even if you’ve been too worried to get tested for ApoE4, new evidence suggests there's a lot that you can do to support your brain health and lower your risk of Alzheimer’s. Read on to learn about the latest research regarding ApoE4 in 2022 and what experts say about how nutrition can play a role.  

If you’re unfamiliar with what ApoE4 means, ApoE is a gene that makes the protein apolipoprotein E, which has many roles in the body including helping to break down and transfer fats. There are several forms (or alleles) of the protein called ApoE2, ApoE3, and ApoE4. Everyone has 2 copies of ApoE (one from each parent), so you may have ApoE2:ApoE3 or ApoE3:ApoE3, for example. Having one (ApoE3:ApoE4) or two (ApoE4:ApoE4) alleles of ApoE4 is associated with a higher risk of developing Alzheimer’s Disease. In fact, a single allele of ApoE4 increases Alzheimer’s risk by about 2-3 fold, while two alleles is associated with 12 fold increase in risk.1

Regardless of your genetics, ApoE4 is not a gene that causes Alzheimer’s, it is only a susceptibility gene, or risk factor. Lifestyle choices like nutrition, exercise, and others allow you to make up for the added risk to support your long-term brain health. 

ApoE4 and the Brain

ApoE4 and the Brain

Diagram adapted from Penny Dacks 

We’re still learning a lot about ApoE4 and what it affects as it pertains to the brain.  Although the exact mechanisms of how ApoE4 contributes to Alzheimer’s are not known, recent research is starting to show the associations of ApoE4 with aspects of Alzheimer’s pathology. These include many of the things that doctors observe in the brains of Alzheimer’s patients including amyloid beta accumulation, neurofibrillary tangles, neuroinflammation, neural network dysfunction, and blood brain barrier breakdown.2

Here are the latest updates through 2022: 

Amyloid Beta Accumulation: Amyloid is a protein that has been long considered a hallmark of Alzheimer’s. You may have heard of amyloid plaques associated with Alzheimer’s; the amyloid protein accumulates in such a way that it forms harmful clumps of protein which prevent proper functioning of the brain and cause neurons to die. Studies have found that carrying the ApoE4 allele is associated with an increased rate of amyloid being produced and forming plaques in the brain. ApoE4 also leads to accumulation of amyloid overtime, while blocking the pathways that remove amyloid from the brain.3-5 

Neurofibrillary tangles: Neurofibrillary tangles are another type of detrimental protein accumulation in Alzheimer’s that come from the build up a of a protein called tau. ApoE4 impacts the tau protein in a way which makes it more prone to develop into the harmful tangles.2 Studies also suggest that ApoE4 and amyloid work together to increase the aggregation of tau into tangles.6

Neuroinflammation: ApoE4 contributes to neuroinflammation by alerting the immune cells of the brain called microglia and astrocytes. These cells release molecules that signal to other cells to activate, further increasing inflammation.2 Neuroinflammation is very harmful to the brain because it releases toxic molecules which can damage our DNA, disrupt the proper functioning of neurons, and damage the blood brain barrier, which is crucial for keeping dangerous molecules out of the brain. 

Neural Network Dysfunction: ApoE4 has a detrimental effect on certain types of neurons which help inhibit activity in the brain. When these neurons are lost, it disrupts the normal pathways, leading to over excitement of the brain, which can contribute to more amyloid and tau accumulation into plaques and tangles.2 Carriers of ApoE4 that have Alzheimer’s have been shown to be overactive in certain parts of the brain, which may contribute to these mechanisms.7

Blood Brain Barrier: The blood brain barrier (BBB) is critical in keeping things out of the brain that don’t belong and that may cause harm. It also allows specific nutrients and particles into the brain that allow it to function properly. The BBB can breakdown or “leak” due to damage caused by inflammation and overstimulation of the brain, meaning it may allow harmful substances into the brain which can exacerbate the damage. DHA is an important fatty acid for brain function, so it is transported across the BBB regularly. Research suggests that APOE4 carriers have a reduction in the transport of DHA across the BBB, which may contribute to the increased susceptibility to Alzheimer’s.8

As you can see, there is a lot that ApoE4 can impact when it comes to brain health and susceptibility to Alzheimer’s Disease. It’s really important for scientists to keep exploring what mechanisms ApoE4 is involved in and how it contributes to the disease. This helps us learn more about Alzheimer’s itself, and more importantly, how to treat or prevent it through targeted approaches. 

How Nutrition Can Help Carriers of ApoE4

ApoE4 does not mean you are going to get Alzheimer’s, and nutrition is at the forefront of how we can take care of our brains specifically for ApoE4. Think of ApoE4 as pliable, and specific nutritional approaches can shift the risk associated with ApoE4. ApoE4 can be targeted through precision nutrition, which involves tailoring our diets and nutritional supplementation to address genetic factors and lifestyle/life history factors that could raise our risk of dementia. It’s a popular area of research as scientists identify major risk factors for diseases and how certain nutrients can address known risk factors and their mechanisms in the brain. 

One expert in the field is Dr. Richard Isaacson, who founded and directed the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and has recently been named director of the new Center for Brain Health at Florida Atlantic University. One of his papers from 2021, published in the Nutrients Journal, gives an in-depth analysis of how precision medicine can be used for ApoE4 carriers.9 This paper is already being cited by more recent publications supporting the role of precision medicine in this field.10

Isaacson proposes 3 different dietary patterns that may target specific mechanisms of ApoE4 to best support the brain. These include a low carbohydrate/low glycemic index diet, a ketogenic diet, and a Mediterranean diet. It’s important to note that these are ideas based on the neuroscience of ApoE4, and not based on any trials conducted in humans to date. However, these approaches are based on current evidence and show promise given the expanding understanding of how ApoE4 affects different processes in the brain.9

Low Carbohydrate Diet: The low carbohydrate or low glycemic index diet focuses on preventing insulin resistance. Insulin resistance is linked to a higher risk of Alzheimer’s independent of ApoE status, but ApoE4 has also been associated with exacerbating the effects of insulin resistance on the brain. Combining evidence from observational human studies in communities who consume small amounts of sugar with mechanistic approaches on how sugars bind to the ApoE protein to impair its function, Isaacson argues that a low carbohydrate diet may prevent some of the mechanisms that allow ApoE4 to contribute to Alzheimer’s.9

Ketogenic Diet: A ketogenic diet is proposed to support ApoE4 by addressing metabolism in the brain. It is thought that ApoE4 may shift metabolism from mainly glucose to another energy source called ketones. The ketogenic diet puts the body in a state where it produces ketones for fuel instead of glucose. In addition, a ketogenic diet can support anti-inflammatory mechanisms to counteract the inflammation triggered in ApoE4 carriers.9

Mediterranean/MIND Diet: Since ApoE4 contributes to neuroinflammation, carriers should prioritize an anti-inflammatory diet that’s also high in antioxidants. Anti-inflammatory foods include leafy green vegetables, nuts and seeds, berries, whole grains, olive oil, fatty fish, and legumes, also components of the Mediterranean and MIND diets. The Mediterranean and MIND diet are well researched for their anti-inflammatory affects. In addition to counteracting the inflammation that ApoE4 contributes to, the MIND diet supports all aspects of brain health and has even been shown to reduce the risk of Alzheimer’s in those that follow the diet closely.9-11

PUFAs: The Rush Memory and Aging Project found that high intakes of omega-3 polyunsaturated fatty acids (PUFAs) help offset harmful effects on the brain of a neurotoxin in people with at least one ApoE4 allele.12

While PUFAs are considered a healthy fat, it’s important for people with ApoE4 not to have a lot of unhealthy fats. Saturated and trans fats contribute to higher cholesterol levels, and ApoE4 carriers have improved cholesterol levels when replacing saturated fats with healthy carbohydrates.13

DHA: DHA, or docosahexaenoic acid, is a specific PUFA found in fatty fish. Alzheimer’s patients have lower levels of DHA than healthy adults, and studies suggest DHA may reduce the buildup of amyloid and tau protein in the brain. ApoE4 carriers break down DHA faster than non-carriers, so it’s important for ApoE4 carriers to have more DHA in their diets or through supplements so it can act on all of the important mechanisms in the brain. Isaacson recommends supplementing DHA at a dose of 2 grams per day for ApoE4 carriers.9 

Alcohol Consumption: Several studies suggest that ApoE4 carriers should limit their alcohol consumption. Any level of alcohol consumption has been associated with an increased risk of Alzheimer’s specifically in people who have ApoE4, and drinking alcohol is associated with a decline in learning and memory in ApoE4 carriers.9

ApoE4 Take-aways

 These examples of personalized nutrition based on the genetic risk factor ApoE4 are just the beginning. As researchers better understand genetic differences and other lifestyle factors, precision nutrition may play a significant role in the prevention and treatment of diseases.10

There is a major group of researchers called the Nutrition for Dementia Prevention Working Group that advocates for precision nutrition and supporting ideas that ApoE4 carriers may benefit from specific nutritional interventions. They propose new clinical trial designs with specific populations, such as ApoE4 carriers, to better test certain nutritional interventions for the prevention of dementia.14

In addition to these nutritional adjustments, people with ApoE4 can support their brain with lifestyle factors such as regular exercise, sleep, using their brain in new ways, and socializing with family and friends. 

There’s a lot of ongoing research into ApoE4 and we learn more every day. Even though ApoE4 may increase your risk of Alzheimer’s Disease, it does not mean that you are definitely going to get Alzheimer’s. You can make nutritional choices today to support ApoE function and diminish the risk associated with ApoE4.

References

  1. Michaelson, D. M., APOE ε4: The most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimer’s Dement., 2014, 10, 861–868.
  2. Koutsodendris, N., Nelson, M. R., Rao, A., and Huang, Y., Apolipoprotein E and Alzheimer’s Disease: Findings, Hypotheses, and Potential Mechanisms. Annu. Rev. Pathol. Mech. Dis., 2021, 17, 73–99.
  3. Toledo, J. B., Habes, M., Sotiras, A., et al., APOE Effect on Amyloid-β PET Spatial Distribution, Deposition Rate, and Cut-Points. J. Alzheimer’s Dis., 2019, 69, 783–793.
  4. Lim, Y. Y. and Mormino, E. C., APOE genotype and early β-amyloid accumulation in older adults without dementia. Neurology, 2017, 89, 1028–1034.
  5. Ossenkoppele, R., Jansen, W. J., Rabinovici, G. D., et al., Prevalence of Amyloid PET Positivity in Dementia Syndromes: A Meta-analysis. JAMA, 2015, 176, 139–148.
  6. Therriault, J., Benedet, A. L., Pascoal, T. A., et al., APOEε4 potentiates the relationship between amyloid-β and tau pathologies. Mol. Psychiatry, 2021, 26, 5977–5988.
  7. Pihlajamäki, M. and Sperling, R. A., Functional MRI assessment of task-induced deactivation of the default mode network in Alzheimer’s disease and at-risk older individuals. Behav. Neurol., 2009, 21, 77–91.
  8. Patrick, R. P., Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease. FASEB J., 2019, 33, 1554–1564.
  9. Norwitz, N. G., Saif, N., Ariza, I. E., and Isaacson, R. S., Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients, 2021, 13, 1362.
  10. Samieri, C., Yassine, H. N., Melo van Lent, D., et al., Personalized nutrition for dementia prevention. Alzheimer’s Dement., 2022, 18, 1424–1437.
  11. Morris, M. C., Tangney, C. C., Wang, Y., Sacks, F. M., Bennett, D. A., and Aggarwal, N. T., MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimer’s Dement., 2015, 11, 1007–1014.
  12. Morris, M. C., Brockman, J., Schneider, J. A., et al., Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults. JAMA, 2017, 176, 139–148.
  13. Griffin, B. A., Walker, C. G., Jebb, S. A., et al., APOE4 genotype exerts greater benefit in lowering plasma cholesterol and apolipoprotein B than wild type (E3/E3), after replacement of dietary saturated fats with low glycaemic index carbohydrates. Nutrients, 2018, 10, 1–13.
  14. Yassine, H. N., Samieri, C., Livingston, G., et al., Nutrition state of science and dementia prevention: recommendations of the Nutrition for Dementia Prevention Working Group. Lancet Heal. Longev., 2022, 3, e501–e512.
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