Studies show that in some people, the inherited genetic variant ApoE4 could not only multiply your risk of developing Alzheimer's disease, but also your risk of experiencing brain bleeds from taking monoclonal antibody treatments for Alzheimer's, like Leqembi.
Alzheimer’s disease affects millions of people worldwide, and as the world’s population ages, that number is going up. But, the exact cause of Alzheimer’s is still unknown. Scientists are probing, among other factors, the role of specific genes — like the genetic variant ApoE4 — in driving Alzheimer’s. ApoE4, for example, is known to increase the risk of developing Alzheimer’s in certain populations. Now, another level of risk is coming into focus: For people with early-stage Alzheimer’s who are taking cutting-edge new disease-modifying Alzheimer’s treatments, this ApoE4 gene also appears to be linked to a higher risk of side effects from these drugs.
These much-discussed new Alzheimer’s treatments are monoclonal antibodies (MABs) designed to target Alzheimer’s protein biomarkers, like beta-amyloid and tau proteins, both of which aggregate in the brains of people with Alzheimer’s, killing off neurons. Aduhelm (which has been taken off the market), and Leqembi (the first fully FDA-approved MAB drug for Alzheimer’s) were both developed to specifically target amyloid. A new anti-amyloid MAB called donanemab is in clinical trials and preparing for an FDA review process as of February 2024.
In medical speak, the side effect that comes along with these anti-amyloid MABs for Alzheimer’s is called Amyloid Related Imaging Abnormalities (ARIA). Colloquially, these ARIA episodes are also referred to as “brain bleeds” — tiny hemorrhages in the brain that are often so small they’re asymptomatic and go completely undetected. On rare occasion, however, they can be serious.
According to behavioral neurologist Dr. Marwan Sabbagh at Barrow Neurological Institute’s Alzheimer’s and Memory Disorders Program, people considering taking these drugs are being asked to take a genetic screening to see if they carry the gene variant ApoE4. This should help them better understand their risks of developing side effects from MAB drugs.
“We know that there are four significant risk factors for progression to dementia: [the] presence of amyloid, significant neurodegeneration on your MRI, bottoming out on your neuropsych testings, and the ApoE4 carrier status,” Sabbagh explained in a Being Patient Live Talk. “So, if you are not an ApoE4 carrier, your risk of progression to dementia is six percent per year. If you’re an ApoE4 carrier, it’s 17 percent per year — a significant predictor of future decline.”
Understanding APOE4 and its influence on on Alzheimer’s risk
APOE4, also known as the “Alzheimer’s gene,” was discovered over 30 years ago and initially associated with heart disease rather than Alzheimer’s.
Approximately one in five people are ApoE4 heterozygous, meaning they carry at least one copy of ApoE4. Two percent of people are homozygous (they carry two copies — one from each parent).
A number of studies have shown that carrying this genetic variant has strong associations with increased Alzheimer’s risk, at least in some racial groups.
Those with a single copy of APOE4 have a lifetime Alzheimer’s risk that’s three to four times higher than people without the gene, Sabbagh said. If an individual has two copies of the APOE4 gene, one from each parent, their lifetime risk of developing Alzheimer’s is dramatically increased, ranging from 13 to 18 times higher than the general population.
“When you break it down in terms of demography,” Sabbagh said, “80 percent of people do not carry the ApoE4, 18 percent have one copy, and two percent have two copies.”
What does ApoE4 have to do with Alzheimer’s disease progression?
ApoE is responsible for carrying cholesterol and similar molecules to the liver from the digestive system, and carriers of the e4 variant may have issues with cholesterol transport in their bodies.
The exact connection between APOE4 and cholesterol transport in people with neurodegenerative diseases is still not known, but APOE4 carriers do tend to accumulate more amyloid in the brain. And that accumulation appears to either cause, or signal, Alzheimer’s disease.
Sabbagh said the presence of APOE4 can impact the progression of mild cognitive impairment to dementia. People with MCI, who have a cognitive disorder but are still independent, face a higher risk of progressing to dementia if they carry the APOE4 gene. “We also know that homozygous [cases] tend to progress more rapidly,” Sabbagh said. “They have more pathology. They have more complications.”
For e4 non-carriers, the risk of progression to dementia is 6 percent per year, while APOE4 carriers are 17 percent-per-year more likely to see their MCI turn into dementia — almost triple the chances.
Monoclonal antibody drugs and genetic risk of side effects
New monoclonal antibody drugs — namely Leqembi (genetic name lecanemab), which is the only such drug available to the general public as of February 2024 — are designed to slow down Alzheimer’s progression by clearing beta-amyloid out of the the brain.
But, like most drugs, they also carry the risk of side effects. These side effects include the aforementioned amyloid-related imaging abnormalities (ARIA) — those tiny brain bleeds that are often so small they often go undetected. People who carry ApoE4, Sabbagh explained, aren’t just more likely to develop Alzheimer’s or see MCI progress faster to Alzheimer’s — they’re also at a higher risk of experiencing ARIA when taking monoclonal antibodies.
“We know that one of the most common complications of these drugs is something called ARIA,” he said. “The biggest predictor of ARIA is your ApoE4 carrier status.”
Accordingly, prescribers and the drug developers of these monoclonal antibody drugs for Alzheimer’s that are now on the market recommend genetic testing is now recommended for risk stratification before administering monoclonal antibodies. For Leqembi, Sabbagh broke down the risk of ARIA based on ApoE4 status.
- For those who don’t carry ApoE4, ARIA risk is 5 percent.
- For those who carry one copy, risk triples, to 15 percent.
- For those who are homozygous (carriers of two copies) risk is six times higher than non-ApoE4 carriers, at a 33 percent chance of developing ARIA.
A Retired Neurologist On His Experience With Aduhelm’s Side Effects
Genetic testing to determine MAB drug eligibility
Sometimes, an individual might consider genetic testing to better understand their Alzheimer’s risk, especially for those with a family history of the disease. Leqembi’s drug label notes the genetic risk associated with the drug, so now, prescribing doctors are also recommending genetic testing to help patients understand whether they’re a good candidate for MAB drugs.
“We went from not talking about [genetic testing] at all to now using it for risk stratification,” Sabbagh said, “because we know that if you’re an ApoE4 double copy, your risk of having complications with the monoclonal [antibody treatments for Alzheimer’s] is quite high.”
He’s not so sure that’s a good idea. There are pros and cons to genetic testing.
“There are many reasons to have genetic testing and to get that genetic information about yourself, but there are many reasons not to,” Virginia Tech’s Dr. Doris Zallen, the author of the book To Test or Not to Test, said in a Live Talk on the pros and cons of genetic testing for ApoE4. “In the books that I wrote about genetic testing, the main point I learned from these people on the front lines, the professionals, and the people with real-world experience, is that preparation is important. You have to think about it and decide whether going ahead with it is right for you.”
Sabbagh, Zallen and other experts agree the decision whether or not to get a genetic test should be weighed carefully, and people may want to consult with a genetic counselor to understand their results. Sabbagh, for his part, isn’t personally a fan of genetic testing just to satisfy one’s curiosity: “I would not do it for risk stratification,” he said of genetic testing for APOE4. “We have to be very tailored and selective in how we use these new tests.”
Especially for asymptomatic individuals, he noted, there are financial considerations, as well: The information learned from the test is permanent — and it can have implications for one’s eligibility or premiums for long-term care insurance, among other things.
“Congress passed a law in 2008 called the Gene Act, the Genetic Information Non-discrimination Act, which says you cannot lose your ability to get health care insurance on the basis of your genetics, but you can lose your ability to get long-term care insurance,” Sabbagh added. “So, we caution people who are not symptomatic to not get tested routinely. When we’re talking about this conversation, I would never draw asymptomatic people. I only draw people who are coming to my clinic, who are having symptomatic complaints.”
Dr. Doris Zallen: The Pros and Cons of Genetic Testing for Alzheimer’s
What’s next for genetics and Alzheimer’s research
With the emergence of gene therapy and potential gene modification treatments, the field is changing fast. Overall, Sabbagh said, the approach to Alzheimer’s is slowly shifting from a focus exclusively on Alzheimer’s treatment to a focus, too, on proactive prevention. Researchers are also exploring the possibility of using genetic information to develop personalized prevention strategies and treatment plans for those at risk of developing Alzheimer’s. But we’re not quite there yet.
Scientists may still be in the dark on what exactly our DNA says about our Alzheimer’s risk — and what exactly we can do with that knowledge to help prevent, cure or slow the disease. One thing they do know: ApoE4 plays a crucial role in determining the safety and efficacy of new treatments.
Watch the full live talk with Marwan Sabbagh here:
Dr. Marwan Sabbagh: What Genes Like ApoE4 Can Teach Us About Alzheimer’s
