People who inherit two copies of a gene variant called APOE4 have a 60% chance of developing Alzheimer's by age 85.
Only about 2% to 3% of people in the U.S. have this genetic profile, and most of them don't know it because they've never sought genetic testing.
But three scientists are among those who did get tested, and learned that they are in the high-risk group. Now, each is making an effort to protect not only their own brain, but the brains of others with the genotype known as APOE4-4.
June: from dismay to hope
A genetic test from 23andMe gave June the bad news in 2023.
"I just felt like the end of the world," says June, who asked to use only her first name out of fear that making her genetic status public could affect her job or health insurance.
June was 57 when she found out. As someone with a doctorate in biochemistry, she quickly understood what the results meant.
"People with our genotype are almost destined to get the disease," she says. "We tend to get symptoms 7 to 10 years earlier than the general population, which means that I had about seven years left before I may get the disease."
At first, June spent sleepless nights online, reading academic papers about Alzheimer's and genetics. She even looked into physician-assisted suicide in an effort to make sure she would not become a burden to her adult son.
Then she discovered online communities like ApoE4.info, which included people with her genetic profile.
"I not only found useful information, I forged deep friendships with people," she says.
June learned about the brain benefits of a Mediterranean diet, exercise, sleep, and stress reduction. And while perusing the Alzheimer's Association website, she discovered an intriguing research project at the University of California, San Diego.
It's an ongoing study to see whether four months of vigorous mental and physical exercise can improve brain health in people ages 50 to 85.
So in 2024, June found herself on a stationary bicycle at UCSD playing a strenuous virtual reality game.
"You're riding a bike and you go through unfamiliar terrain where you need to make turns," she says. "So you really have to use all your cognitive reserve."
The study also involved a series of MRI scans and cognitive tests.
"That was absolutely a game changer because I not only got to watch my brain in action, I was able to develop really effective strategies of retaining my memory," she says.
Since participating in that trial, June has been advocating for federal funding for Alzheimer's research and urging the Food and Drug Administration to consider drugs that might benefit people who have the APOE4-4 genotype.
"I realize that being APOE4-4 is not the end of the world," June says. "There's so many things we can do."
David Watson: drug discovery
Lots of mental and physical activity might delay the symptoms of Alzheimer's, says David Watson, a neuropsychologist and CEO of the Alzheimer's Research and Treatment Center in Florida.
But that's not enough for him and other people who carry two copies of APOE4 variant.
"Any of these things that we can do preventively, they're going to be helpful," Watson says. "But are they going to override genetics? No, they're not, unfortunately."
Watson, now in his mid 50s, learned his genetic status about 25 years ago after seeing several family members develop Alzheimer's.
He decided to devote his career to running clinical trials of Alzheimer's drugs in hopes of finding one that might protect his brain.
That effort helped get two new drugs (lecanemab and donanemab) on the market. Unfortunately, Watson is not a good candidate for either drug.
Lecanemab and donanemab are both monoclonal antibodies that remove sticky amyloid plaques from the brain — a hallmark of Alzheimer's. But in people with Watson's genetic profile, the drugs often cause dangerous swelling or bleeding in the brain.
"If someone is APOE-4-4, they should probably should not go on a monoclonal antibody targeting amyloid," he says. Or if they do, it should be "very cautiously with additional counseling," he says.
So Watson has been focusing on an experimental drug that's meant specifically for people with two copies of APOE4. The pill, which was tested in some patients at his center, is designed to interrupt the process that leads to amyloid plaques, rather than removing plaques that have already formed.
"This particular compound actually showed remarkable findings," Watson says.
The drug, made by Alzheon, didn't cause brain swelling or bleeding. And it prevented brain areas associated with memory from shrinking the way they usually do in Alzheimer's.
But in a large trial, the drug failed to clearly show it could slow down cognitive decline in people who already had Alzheimer's symptoms.
Even so, Watson thinks the Alzheon drug has potential.
Some study participants who've stayed on the drug seem to be "holding their own" instead of getting worse, Watson says. And blood tests of these participants suggest that "we're really making a difference in keeping neurons alive," he says.
Wendy Nelson: Going very public
When a genetic test from 23andMe showed that Wendy Nelson carried two copies of the APOE4 variant, she went quiet.
"I just sort of didn't want to tell anybody at first," she says. "I really just kept the results to myself."
Nelson, 54, is a PhD scientist in the biotech industry. So she knew what the results meant. But she didn't know what to do with them.
She was already taking part in the sort of activities that might protect her brain. "I'm a triathlete, a hardcore hiker, I eat healthy," she says.
So when she learned her status in 2022, about the only changes she could make were to stop drinking and start a cholesterol drug.
Then, one of Nelson's biotech contacts put her in touch with a podcast about dementia and brain health. They asked her to do an interview. She agreed.
"That was at the point where no one knew what my status was," she says."But in my mind, I was thinking, well, who's ever going to see this?"
Lots of people, it turned out.
Pretty soon, Nelson found herself on other podcasts, being interviewed by Reuters, and eventually appearing on TV news. She began working with advocacy groups including the APOE4-4 Alzheimer's Alliance.
Nelson says being a public face for the APOE4-4 community gives her a chance to educate the public about a genetic profile that may affect millions of people in the U.S. It also gives her a forum to advocate for more basic research on Alzheimer's.
And just a few weeks ago, Nelson got a chance to meet with officials of the Food and Drug Administration to talk about Alzheimer's drugs for people like her.
"I provided my seven minutes of testimony to the to the FDA, which was my plea for more options," she says, "because I don't feel like I have anything out there right now."
But Nelson, like June and Watson, says people in the APOE4-4 community can change that by pushing for more research and an easier regulatory path for drugs that might help.
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