What You Need to Know About ApoE4, An Alzheimer’s Risk Gene
The pros and cons of getting tested for this common variant
Hello, everyone. I write to you from San Diego where I am visiting my mom. A lot of you have asked me how she’s doing and I really appreciate that. Maybe someday I’ll be able to write more about this stage of Alzheimer’s. For now, all I can say is that meeting her needs at home is getting increasingly dificult. I’m sure many of you caring for people with Alzheimer’s or dementia can relate!
Today we are talking about an important risk factor for late-onset Alzheimer’s: carrying one or two copies of the gene variant ApoE4.
ApoE4 burst onto the world stage last year when actor Chris Hemsworth found out he was a carrier on the National Geographic television series Limitless. In the program, he learns that having two copies of ApoE4 increases his risk of Alzheimer’s later in life tenfold or more.
The most crucial thing to understand about ApoE4 is that having one or even two copies does not mean you will definitely develop Alzheimer’s. This is why ApoE4 is called a “risk gene.” It modifies risk, but the gene itself is pliable, meaning it’s possible to lessen its harmful impact on the brain. In fact, things like exercise and following a Mediterranean-style way of eating have the power to turn down the volume of ApoE4.
Before we go into that, let’s talk about the genetics of Alzheimer’s, what this gene does, how common it is, and what it means if you carry one or two copies.
Genetics and Alzheimer’s 101
One of the most prevalent myths about Alzheimer’s is that it’s always genetic, meaning you get it because you inherited a gene for it from a parent. It’s true that about 50% of all people with Alzheimer’s have a genetic risk factor, but less than 2% of all people got it purely through a genetic mutation. (That’s the rare, early-onset Alzheimer’s, mentioned below.) That being said, it’s very common to carry a copy of ApoE4—between 15 and 25% of the population carries one or two copies.
It helps to know there are two general categories of genes that influence disease.
Risk genes increase the likelihood of developing a disease but do not guarantee it will happen. There are several genes that increase the risk of Alzheimer's. ApoE4 is the first risk gene identified and remains the one with the strongest impact on risk.
Deterministic genes directly cause a disease, guaranteeing that anyone who inherits one will develop a disorder. For example, if you inherit the gene for sickle cell anemia, cystic fibrosis, or Huntington’s disease, you will get the disease. Scientists have found rare genes that cause Alzheimer's in only a few hundred extended families worldwide. These genes, which are estimated to account for 2% or less of Alzheimer's cases, cause familial early-onset forms in which symptoms usually develop between a person's early 40s and mid-50s. The vast majority of individuals with Alzheimer's have late-onset disease, occurring at age 65 or later.
ApoE4 is a risk gene
ApoE is a gene that has evolved over time to have three different variants, called alleles: ApoE2, ApoE3, and ApoE4. Everyone inherits one ApoE allele from each parent. You could have an ApoE2 and an ApoE3, for instance, or a combination of ApoE3 and ApoE4.
It’s the ApoE4 allele that is considered a risk gene for late-onset Alzheimer’s. Possessing one copy of ApoE4 increases the risk of developing Alzheimer’s later in life by three- to five-fold; having two copies increases risk tenfold, and some studies say up to fifteen-fold. If you have one or two copies of ApoE2, however, it is actually a good thing—it protects you from Alzheimer’s.
While ApoE4 is known as an Alzheimer’s risk gene, it exerts its effect on the brain indirectly by how it moves blood cholesterol into cells. A glitch in the gene’s structure creates a faulty transport mechanism. The brain cells bear the brunt of the problem, getting too much of the type of cholesterol known to cause damage to blood vessels (LDL) and not enough docosahexaenoic acid (DHA)—the brain-repairing omega-3 fatty acid.
All of these gene variants affect processing or production of beta-amyloid and tau, proteins that damage the brain over time, culminating in Alzheimer’s.
How common is ApoE4?
As mentioned above, these gene variants are common: between 10 and 25% of Americans carry at least one copy of ApoE4. Carrying two copies, as in Hemsworth’s case, is more rare: under 2% of the population. It is estimated that 1 in 25 people in the U.S. know their carrier status, thanks to home genetic testing kits (such as 23andMe) that make it easy to check.
Question for you:
Do you know if you carry an ApoE4 gene?
If so, did you get tested through a home kit or at the doctor’s office?
Where you live impacts ApoE4’s expression
Environment determines whether or not an ApoE4 gene has a driving effect on long term brain health. For example, we know the Mediterranean diet and lifestyle is associated with cognitive health and longevity. Southern Italians who carry an ApoE4 and live in Italy do not have an increased risk of Alzheimer’s. In fact, they have the same chance of living to be in the oldest 1% of the population as their neighbors who don’t carry an ApoE4. How can this be? Researchers are studying the interplay between environment and this gene’s expression.
Another example: ApoE4 is common in people with West African ancestry yet does not contribute to more cases of Alzheimer’s in Nigeria. In the Indianapolis–Ibadan dementia project of 4606 people of African descent, ApoE4 carriers living in the U.S. had twice the incidence of Alzheimer’s as those living in Nigeria.
Black Americans have twice the Alzheimer’s risk as White Americans. Studies suggest a myriad of environmental factors are partially to blame. “Weathering” is a hypothesis to explain the accelerated brain aging of Blacks in America. This brain imaging data takes into account the accumulation of racial stressors over time due to discrimination, poverty, poor access to brain-healthy food, residential segregation, pollution, and fears about personal safety.
ApoE4 has a greater impact on women
It has been known for decades that women are more likely to develop Alzheimer’s than men. Two thirds of persons living with Alzheimer’s are female. One way researchers are investigating why women are more vulnerable to this neurodegenerative disease is to study the biological differences between women’s and men’s brains. Why, for example, do men and women seem to be on different timelines of brain aging?
As it turns out, women’s brains metabolize glucose differently than men’s, which becomes glaringly apparent during the menopausal transition. (I wrote a detailed article about this here, excerpted below.) Women’s brains also attract different pathological proteins that can create an inflammatory, dementia-provoking state. Female ApoE4 carriers have unique challenges getting enough neuroprotective nutrients to the brain, especially DHA, which may explain their heightened vulnerability to brain aging.
As a woman ages, her ApoE4 allele impacts her brain in different ways. As a young woman, ApoE4 actually confers a cognitive advantage, helping her excel at memory tasks, processing speed, and verbal fluency.
By middle age, however, having ApoE4 becomes a disadvantage, making it harder for these women to perform cognitive tasks. Not only is a female ApoE4 carrier’s glucose metabolism impaired, she has difficulty accessing ketones—an alternate energy produced by the liver when the body goes into starvation mode. The brain is usually metabolically flexible enough to shift between using glucose and ketones. For the perimenopausal ApoE4 carrier, however, both pathways are impaired—a recipe for brain fog that may set her up for Alzheimer’s, too.
In this study of 1,178 women, researchers looked at the brain health benefits of taking HRT in two groups of women: those who carry one or two copies of the ApoE4 risk gene for Alzheimer’s, and those who do not. They compared HRT users with non-users, and noted whether HRT was started early or late in the perimenopausal transition. Participants were followed with cognitive testing and brain imaging over time.
In the study, the ApoE4 carriers who took HRT starting early in the perimenopause had the best results. They performed better on cognitive tests, especially word retrieval and delayed memory tasks. They also had larger brain volume in key areas like the hippocampus (important for short term memory) and the amygdala (which has a central role in anxiety and stress response). I wrote about talking to your physcian about HRT here.
Finally, male and female ApoE4 carriers seem to be on different brain health trajectories. In a woman, having an ApoE4 is more likely to accelerate the path to Alzheimer’s. This interplay of risk posed by getting older, being female, and carrying an ApoE4 variant has been called the “Triad of Risk for Alzheimer’s Disease” in this paper, and is currently an area of intense investigation.
ApoE4’s should know about KLOTHO, too
Here’s another twist to the ApoE4 story: researchers at Stanford have discovered a gene variant—KLOTHO—that reduces the impact of ApoE4. So while carrying one copy of ApoE4 ups Alzheimer’s risk, having one copy of KLOTHO reduces it by 30%. It gets even more complicated in that two copies of KLOTHO are not better than one. Double KLOTHO carriers don’t have the same Alzheimer’s risk reduction.
All of this is to say that this is a rapidly evolving topic. As more gene variants are discovered, so will our ability to modify risk factors to delay or prevent the development of Alzheimer’s.
You’ve tested positive for ApoE4. Now what?
As I mentioned above, the most crucial thing to understand about ApoE4 is that having one or even two copies does not mean you are going to get Alzheimer’s. The good news for ApoE4 carriers is that researchers are figuring out how to turn these gene variants “off” with lifestyle interventions. Ideally people who carry an ApoE4 variant will have a team of specialized medical professionals—physicians in the field of precision medicine—to guide them with recommendations as the science evolves.
Precision nutrition guidelines for ApoE4
It’s also important to understand that no long-term human studies have been done to determine the best way to eat if you carry an ApoE4 allele. What we do have is this: the latest guidelines according to Alzheimer’s experts in ApoE4. While this paper goes into a lot of scientific detail, it also lists current recommendations on the neuroprotective foods, dietary patterns, and supplements that may optimally shut down ApoE4’s impact on the brain.
Below, I summarize the key recommendations from this paper. If you carry an ApoE4, however, I urge you to read the entire paper, share it with your health care team, and determine the approach that makes the most sense for you as an individual.
Recommended dietary pattern for ApoE4 carriers
