June 7, 2024 – If you found out you are almost certainly to have Alzheimer’s disease some time in the future, what would you do?
What could you do?
That’s the question many researchers and doctors are facing after a group of Alzheimer’s disease researchers recently suggested that genetics alone could identify in advance up to 20% of the people who are ultimately diagnosed with the devastating form of dementia.
“The real question is – and the risk is – if you identify people at that stage, what are you going to do about it, because we don’t fully know the spectrum of courses that will unfold over time,” said geriatric psychiatrist Marc E. Agronin, MD, an Alzheimer’s expert and the chief medical officer at the Frank C. and Lynn Scaduto Mind Institute at Miami Jewish Health in Florida.
The proposal poses a challenging question of whether to test people for the specific gene variant APOE4, which has long been linked to Alzheimer’s disease. Carrying two copies of APOE4 happens only in about 2 of every 100 people, so it’s uncommon. But the new study, published in May in the journal Nature Medicine, found that 95% of carriers developed signs of AD in their brain or body fluids. And those signs were evident, on average, nearly 20 years before an Alzheimer’s diagnosis.
But not everyone with two copies of APOE4 had other clinical symptoms, which usually are the trigger for an Alzheimer’s diagnosis, like severe memory, mood, and thinking problems. Because APOE4 testing is not typically recommended as part of preventive care, carriers mostly don’t know they have this variant, even if they are trying to do proactive things like diet and lifestyle changes to cut their chances of getting Alzheimer's.
Biomarkers Abound in APOE4 Markers
The apolipoprotein E gene (APOE for short) is linked to Alzheimer’s risk because it's involved in the body’s process for carrying cholesterol and other fats in the bloodstream. People can have different versions of the APOE gene, getting one input from each parent. Up to 20% of people have one copy of APOE4, and just 2% of people have two copies. People with two copies of APOE4 are referred to in scientific terms as “APOE4 homozygotes.”
The Nature Medicine study examined data from 3,300 donated brains and the health data of about 10,000 people to see how having two copies of APOE4 may be linked to telltale signs of Alzheimer’s in the brain and differences in disease and symptom progression based on a person’s age. Overall, the study included the brains of 273 people who had two copies of APOE4, and the health data of 519 people who also had two.
The researchers found that, on average, the brains from people who were APOE4 homozygotes had evidence of Alzheimer’s changes beginning around age 55. Symptoms began on average at 65, mild problems with thinking skills were diagnosed around 72, and then dementia was diagnosed around age 74.
In all, the researchers found a consistent and progressive story told by biomarkers and brain changes revealed through brain imaging and through lab tests of body fluids. All of the disease progression markers typically occurred 7 to 10 years earlier for APOE4 homozygotes, compared to people with other APOE variants. The consistencies in the data prompted the researchers to suggest that carrying two copies of APOE4 is “deterministic” of developing AD, and not merely predictive. If the suggestion becomes widely accepted, it could make Alzheimer’s one of the most common inherited diseases in the world.
“For me, what's really important here is the promise that perhaps we could treat people before symptoms, particularly those who already have the disease in their brain,” said Reisa Sperling, MD, a neurologist and Alzheimer’s researcher at Massachusetts General Hospital in Boston. Sperling wasn’t involved in the study but spoke at a media briefing organized by the Nature Medicine.
Genetic Test Results Are Not a Guarantee
Experts cautioned that the new study’s findings have large limitations that should give pause to people who may read about APOE4 and seek testing, which is widely available on the commercial market.
The data for the study primarily included only White people of European ancestry and was entirely sourced from databases focused on Alzheimer’s research.
“This is an exciting time in the Alzheimer’s research field. Scientists are regularly developing and investigating exciting new ideas. But at this time, the notion proposed in the Nature Medicine paper is simply a provocative idea that needs to be replicated and confirmed, in particular in study populations that more accurately reflect the diversity of people living with Alzheimer’s disease,” said Heather M. Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association.
Erin Coffman, MS, a clinical genetic counselor at the University of Texas Southwestern’s medical genetics clinic in Dallas, agreed that the study’s limitations are important. She doesn’t expect the paper to change how she counsels patients. She would not be surprised, though, if more people start asking her about APOE testing.
“I really do think this could spark an initial interest to meet with a genetic counselor to have that informed conversation about their risk,” said Coffman, noting that has happened amid other high-profile news stories, such as when celebrities are diagnosed with disorders that have a genetic link.
The American College of Medical Genetics and Genomics doesn’t recommend predictive APOE testing, and she said it’s rare that people choose to get it after having a conversation with her. Most of her conversations about APOE4 test results are with people who set up a meeting with her because they already have results in hand.
“A lot of people are just curious because they are information seekers, and a lot of those individuals have been doing direct-to-consumer testing, and then they may come to me to discuss their test results,” Coffman said.
She may place a referral to a neurologist if a person has concerns, or they may simply discuss ways to reduce overall risk of having Alzheimer’s.
“This is not something that would guarantee that this would happen for them in their lifetime, because we don’t really know how long each of our lifetimes is going to be,” Coffman said. “This is something where the counseling is mainly to make sure people do know the risk, but also making sure that they have that sense of hope and making sure they can know they can limit other risk factors.”
Agronin emphasized the importance of APOE4 testing being done in a supportive context.
“My concern is that if the tests are done outside of the setting of genetic counseling or working with experts in Alzheimer’s disease, it can be misinterpreted or there can be overreactions to it, without the necessary support,” he said. “Because without question, the study points to the fact that if people are homozygous for APOE4, there really appears to be an inevitability of developing Alzheimer’s disease, where in the past we talked more just about the higher risk and we left it at that.”
Susan D. Klugman, MD, president of the American College of Medical Genetics and Genomics, said the organization may look deeper into how the new study may impact the organization’s recommendations for APOE testing.
“The findings in this paper are intriguing and warrant further evaluation from national societies, including our own,” she said, adding that any consideration to update a guideline would only come after an extensive review and not from a single study.
“Large-scale APOE genotyping and the disclosure of the results can be problematic, with many ethical, legal, and financial concerns,” Klugman cautioned.
The Outliers: Some Never Developed Symptoms
The study in Nature Medicine reported that not everyone who had two copies of APOE4 had the exact same disease progression. Those outliers are areas that experts said pose key questions for future research.
“It is important to recognize that some people get to an advanced age with two copies of APOE4 and do not get dementia,” Snyder said. “It is not predetermined or ‘locked in’ that they will experience dementia due to Alzheimer’s disease, even if they have the brain changes that are characteristic of the disease.”
Talking about those variations in the study’s findings during a genetic counseling session would be important, Coffman said.
“Even this study said the age of onset was really variable. It could be around 40, but it also could be up to around 81 or 82, and not everyone even went on to develop symptoms,” she explained.
If a middle-aged person came into the clinic asking for genetic testing but had zero symptoms, Agronin said that he would not refuse to give them an APOE test.
“Here is what’s changing, and this study is really pushing us in this direction: Somebody comes in and is in their 40s and 50s, and they want to know their genetics. They might have zero symptoms, but let’s say they are homozygous for APOE4,” he said. “So we know from the study that as people get into their mid-50s and above, they ostensibly would have Alzheimer’s pathology in their brain, and by age 65, three-quarters of them already have a positive PET scan, so they really are in a different category.”
Since this case would be linked to genetics, the news may not come entirely as a surprise.
“The people who come in and who have a strong family history, many of them are already prepared and they are eager to take action,” said Agronin, whose clinic also offers an Alzheimer’s disease prevention program. The program focuses on living a brain-healthy lifestyle and provides coaching to change or reduce risk factors.
“I’ve shifted the language I use and my approach over the past 10 years,” Agronin said. “I never talk about anyone suffering from a disease, I talk about people living with neurocognitive changes, because that’s indeed what they’re doing.”
