APOE4 is the most common genetic variant associated with Alzheimer’s disease.
People with one copy of APOE4 have roughly three times the risk of developing dementia. Those with two copies carry, on average, 12 times the risk, though that can vary widely depending on ethnicity, sex and other genes. The variant is linked to an earlier onset of Alzheimer’s symptoms, as well.
For APOE4 carriers, who represent an estimated 20 to 25 percent of the population, that information can be terrifying. But experts emphasize that having the variant, especially only one copy, does not guarantee someone will develop dementia.
People “find out they have an E4 and they think they’re doomed,” said Dr. Hussein Yassine, a professor of neurology at the University of Southern California’s Keck School of Medicine. “And that’s not true.”
In fact, research suggests that lifestyle factors — whether you smoke, how often you exercise, what you eat — may be especially important for APOE4 carriers when it comes to altering their risk of dementia.
How APOE4 Raises Your Risk
There are three versions of the APOE gene, each associated with a different risk of Alzheimer’s: APOE2 lowers the risk, APOE4 raises it and APOE3 (the most common) is considered neutral. People inherit two copies of the gene, one from their mother and one from their father.
The protein that the APOE gene produces, apolipoprotein E, is involved in shuttling cholesterol and other fats around in the brain and the rest of the body. For reasons scientists don’t fully understand, the E4 version of the protein disrupts other important brain processes — including the brain’s immune response and the removal of the protein amyloid-beta — which in turn are linked to Alzheimer’s.
Experts used to think of APOE4 as specifically tied to Alzheimer’s risk, but now they see it as related to brain sensitivity more generally, said Lisa Delano-Wood, a professor of psychiatry at the University of California San Diego School of Medicine. The variant “doesn’t cause Alzheimer’s, but it seems to make the brain more vulnerable to a broad range of what we call second hits,” or other behaviors and conditions that can harm the brain, she said. “And so APOE4 isn’t destiny; in a sense, it’s susceptibility.”
For example, research suggests APOE4 carriers have worse outcomes, including an increased risk of Alzheimer’s, following traumatic brain injuries. The same is true with other things that can harm the brain, like smoking, heavy drinking, cardiovascular problems like high blood pressure and certain medications, most notably anticholinergic drugs, such as antihistamines.
“You have to think about E4 as an enhancer,” Dr. Yassine said. It’s the “first hit” to brain health, and when you get a second hit, “the system is less capable of dealing with it.”
How to Lower Your Risk
While people with the APOE4 variant have more to lose from behaviors that increase dementia risk, they may have more to gain from healthy habits.
One recent analysis, which incorporated data from three clinical trials, looked at how healthy behaviors, largely focused on nutrition and physical activity, affected older adults’ cognition. The interventions didn’t completely close the gap in cognitive trajectories between APOE4 carriers and noncarriers, but people with the variant benefited at least as much, and in some cases more, than people without the variant.
Dr. Ari Solomon, a professor of neuroepidemiology at the University of Eastern Finland who conducted the analysis, said that when he was in medical school, if a patient carried APOE4, the sentiment was, “we can’t help you.” But now studies show there are things that people can do to lower their risk, he said.
”It’s not a guarantee that somebody won’t ever develop dementia,” Dr. Solomon added, “but there is enough to say that it may have a benefit.”
Exercise appears to be especially effective. One older study from Finland found that sedentary APOE4 carriers were five times more likely to develop Alzheimer’s than noncarriers who were physically active. But for people with the gene variant who exercised at least twice a week for 20 to 30 minutes, their risk was threefold lower.
Diet may also be important for lowering risk, though it’s unclear which type is best for APOE4 carriers. Some research found a Mediterranean-style diet was most beneficial, and that unsaturated fats, like those from fish and nuts, were protective against cognitive decline, while saturated fats from animal products were harmful. However, another study suggested APOE4 carriers who ate more meat actually fared better.
Activities that benefit a person’s emotional, social and cognitive health may also be protective. One recent study found that volunteering slowed cognitive decline in people with the variant.
Not every study on lifestyle changes shows a specific benefit for APOE4 carriers. Laura Baker, a professor of gerontology and geriatrics at Wake Forest University School of Medicine who led a large trial aimed at reducing dementia risk through healthy behaviors, said in her research, people with and without the variant tend to see comparable improvements.
But, she said, “There’s no downside to working toward a healthier body in the interest of protecting brain health.” So, she added, “why wouldn’t you?”
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