SAN DIEGO — Everyone at the meeting had one thing in common: a ticking time bomb buried in their DNA.
The engineers, physicians, financiers, and farmers gathered here this month all had learned through genetic testing that they carry a copy or two of APOE4, an allele of the gene APOE that substantially increases their risk of developing Alzheimer’s. It’s a disease with no good treatment, and no good prevention strategy. So carriers scour the internet to devise their own tactics for keeping their brains healthy: a high-fat diet. Episodic fasting. Oils. Supplements. Regular blood tests to monitor a specific type of cholesterol. Exercise, exercise, exercise — even including barefoot cartwheels across the conference room floor.
Some of these ideas have modest scientific backing; others are more speculative. All are fair game for APOE4 carriers who are desperate to ward off the frightening tumble into dementia that they’ve seen afflict far too many of their relatives.
The advent of low-cost genetic sequencing has opened up the secrets of our DNA — allowing us to learn about our Neanderthal origins, our tendency towards lactose intolerance, even (perhaps) our risk of developing tendon injuries when we work out. But that knowledge comes at a cost: Science often can tell us what diseases we’re predisposed to get, but not how to forestall them.
A simple Google search about Alzheimer’s prevention turns up countless prospective remedies — and few answers. One site might suggest eating more blueberries, while another pushes coconut oil, and a third touts the virtues of oily fish. Amid the cacophony, the carriers gathered here for an APOE4 support group have, in effect, turned themselves into miniature science experiments, which they dub n=1 studies.
“It gets overwhelming, in terms of, ‘What the heck do I do?’” said Theresa, an APOE4 carrier who did not want her full name used to protect her privacy. “That’s one of the benefits of this APOE4 group: We discuss all these things, and try and clarify them to make sense of it all.”
Finding out you carry APOE4 can be terrifying. About 1 in 10 adults will develop Alzheimer’s by the age of 65; by age 85, that risk goes up to 50 percent. Carry one copy of the allele, and you have triple the likelihood to develop late-onset Alzheimer’s disease. Carry two copies, and your chances go up twelvefold.
Sisters Betty Gleason Lacy and Shelley Alvarado are staring down that grim genetic math.
They have a deep family history of Alzheimer’s: Their mother, grandmother, and great-grandmother all developed the condition. Their father, too, has dementia, though it likely has a different root.
Each sister carries a single copy of APOE4. Their brother carries two. The sisters know how the disease can slowly take hold; they’ve seen their parents — once headstrong, accomplished, and independent — fade into shadows of their former selves.
The pharmaceutical industry can offer no real hope: Drug after drug after drug has flopped in clinical trials. So Lacy is doing her own research, crisscrossing the country as a citizen scientist, attending conferences like this one to try to gain new insights from others with the APOE4 variant.
“I feel very compelled to demystify this disease,” Lacy said. “We do not have to live with the old myth that there’s no hope, and there’s no cure.”
The problem, of course, is that it’s not a myth: There is no cure for Alzheimer’s.
And while many APOE4 carriers believe that dietary changes offer hope for preventing the disease, it’s been difficult to test that theory, said Dr. Rudolph Tanzi, director of the genetics and aging research unit at Massachusetts General Hospital. He’s working with a company to develop a supplement for brain health, but said it’s much harder to find funding to test low-cost lifestyle interventions, such as cutting out carbohydrates.
“These trials are expensive,” he said. “If no money’s to be made with a little white pill, who’s going to fund them?”
Theories abound, but the science is scant
A quick science lesson: The APOE gene gives the body instructions on how to produce a protein called apolipoprotein E. This protein ultimately helps regulate cholesterol levels in the blood. There are three major variants to the gene, called e2, e3, and e4. They only differ slightly.
But the “very, very tiny” difference in APOE4 “has a profound effect on the way the protein is handled,” said Dr. Robert Mahley, an Alzheimer’s researcher at the University of California, San Francisco, who first discovered the APOE protein about 17 years back.
It’s still largely not known how APOE4 increases the risk of Alzheimer’s. It is, however, associated with a buildup of protein clusters, called amyloid plaques, that accumulate in the brains of people with the disease. These toxic proteins can cause neurons to die, causing symptoms to progressively worsen.
The disease has a number of co-risk factors — such as diabetes, smoking, and hypertension — so Mahley suggests that his patients control their cholesterol, maintain normal blood pressure, and aggressively treat their diabetes in hopes of reducing their chances of getting Alzheimer’s. But beyond such measures, science offers few answers to those with APOE4.
“These trials [of various diets] are expensive. If no money’s to be made with a little white pill, who’s going to fund them?”
Dr. Rudolph Tanzi, Alzheimer's researcher
One approach that’s circulated heavily in the community is the low-carb, high-fat “ketogenic diet.” Much like the popular Atkins diet, it’s meant to retrain the body to use fat, rather than glucose, as its primary source of fuel.
Ketogenic diets first proved useful in the 1920s to prevent seizures in some patients with epilepsy — hinting that the diet may have a broader neuroprotective effect. The diet has not been shown to improve cognition in people with APOE4, but it remains popular among carriers of the genetic variant, who hope it could help stave off dementia.
Others have adopted episodic fasting. They draw hope from what’s known as the Nigerian paradox: Although the APOE4 allele is frequently found among elderly Nigerians, they’re not at increased risk of Alzheimer’s. African-Americans, by contrast, are just as likely to have the APOE4 allele, but develop the disease at much higher rates.
The biggest difference in the populations is that the Nigerians have a lower incidence of cardiovascular disease — as well as lower levels of fats and cholesterol in their blood. So it’s possible that the Nigerian diet, which can include periods of low calorie intake, might protect against dementia. (There is some more general evidence that fasting can help prolong life, though the majority of the work has been conducted in animals.)
The concept of episodic fasting has won over George, a 62-year-old from Colorado who asked that only his first name be used to protect his privacy.
He watched his mother decline from Alzheimer’s and then learned in 2009 that he carried the APOE4 gene. As it turns out, so does his wife.
They consult regularly with Dr. Steven Gundry, a cardiothoracic surgeon by training who has written two diet books and sells a line of dietary supplements. (He has also backed actress Gwyneth Paltrow’s often less-than-scientific wellness site, Goop.) Among his controversial tips: Avoid foods containing lectins, such as tomatoes, peppers, beans, lentils, and pasta.
George said the diet resonates with him: “I want to go back to the way our ancestors lived.”
Every two weeks, he fasts for four to five days. He religiously tracks his food intake, and is constantly on the move. (He was the one doing cartwheels across the conference room to keep up his cardio.) George also regularly pays out of pocket to test a number of blood biomarkers, including sdLDL, a type of cholesterol that Gundry believes is a primary “mischief maker” in people with the APOE4 genetic variant. If George doesn’t like the number he sees on the lab readout, he tweaks his diet to try to raise or lower his sdLDL.
“I’m probably more crazy than most people,” George conceded.
Mainstream scientists point out that such theories, while intriguing, are still far from validated. Gundry, for instance, said he has some anecdotal evidence but has published no rigorous clinical trials to back his views on using diet to forestall Alzheimer’s.
And while there’s a whole cottage industry of books and games that promise to help preserve brain health, there just isn’t a lot of evidence behind it.
“The data, I must say, is soft,” Mahley said. “It’s very hard to prove these lifestyle things. Lifestyle is a soft science, and nutrition is a soft science — because people respond to diets very differently.”
Fighting to save every brain cell
Outside of sharing some DNA, sisters Lacy and Alvarado don’t have a lot in common. Lacy’s a left-leaning psychiatrist, and a bit of a Buddhist. Alvarado, a surgical nurse, is fairly conservative and a devout Christian. They were never all that close, until recently — when they found out that they both carry APOE4.
Having watched their parents decline, they know all too well what that could mean.
Their father, a World War II vet, was a physician, and their mother helped found a school for autistic children in Long Beach, Calif. That school, Alvarado joked, was her mother’s fourth child — written in equally in her will. But their parents’ memories of their accomplishments have largely all gone now, and the sisters have been powerless to halt the progression of dementia.
Lacy tried to change her mother’s diet so that it more closely matches her own high-fat, low-carb approach — heavy on leafy greens, fish, nuts, and plant-based oils — but that’s proven near-impossible in her mother’s group home. So the daughters have decided that the next time their mother falls ill, they’ll let the infection take its course rather than fighting to keep her alive. That’s what she would have wanted.
In the meantime, they’re sharing tips with new friends at the APOE4 meetup, which was organized to coincide with Low Carb USA, a dietary conference in San Diego.
“We’re the canaries in the coal mine,” Alvarado said.
The meetup was conceived by Julia Gregory, a former marriage counselor who discovered five years back that she carried two copies of the APOE4 gene. She was just about to turn 50, and had sent in a saliva sample to the genetic testing service 23andMe. She found her results were alarming, to say the least. And the advice she was given was certainly lacking: Her doctors could offer few suggestions beyond crossword puzzles and square dancing to prevent the onset of Alzheimer’s.
So Gregory began to commiserate — and brainstorm — with the fellow APOE4 carriers she found on 23andMe’s forums.
The participants shared lifestyle tips and research insights. Eventually, Gregory formalized the group into a nonprofit called APOE4 Info. Gregory now runs the organization full time, moderating the site’s online forum and consulting individually with people who have recently learned of their APOE4 status.
She, too, experiments with her diet, but in moderation. “I’m nowhere as zealous or strict about my diet as some of our members,” she said. “The idea of living life without a cucumber or tomato is depressing to me.”
“I’m nowhere as zealous or strict about my diet as some of our members. The idea of living life without a cucumber or tomato is depressing to me.”
Julia Gregory, founder of APOE4 Info
This year’s meetup drew a few dozen APOE4 carriers from around the world, who attended lectures suggesting a link between diabetes and Alzheimer’s and talked up their own experiments, often with technical proficiency that might rival a decorated neuroscientist.
“I think I’m a much healthier person after having gotten involved in this group,” said Diana Ross, 83, a carrier who attended the meetup. She’s cut down on carbs and boosted her intake of vegetables and protein, and said her doctor has been pleased with the results.
Members also discussed the broader implications of carrying APOE4, including the possibility of genetic discrimination. Alvardo, the surgical nurse, worries about how her peers will respond if she slips up at work: Will her colleagues read a momentary lapse of memory at face value, or as a sign of something deeper?
As for Lacy, these days, she is expanding her psychiatric practice to serve a more geriatric population — by counseling patients on the lifestyle and dietary tips she’s trying out herself. It’s still a long shot, but she’s confident that these lifestyle changes will help.
“I feel motivated,” she said, “to save every brain cell I can.”