Age is the greatest risk for Alzheimer’s disease, and Alzheimer’s risk increases in people steadily from the age of 65 upward. That hard fact translates to 7 million people who suffer from the neurodegenerative disease and the expectation that the number could nearly double by 2050. 

The statistics may also lead some to believe that Alzheimer’s disease is an inevitable outcome of aging. That fatalistic view might be strengthened by research that examines the role genetics plays in Alzheimer’s disease. One recent example is a study whose authors announced that they had established a new genetic form of Alzheimer’s disease.   

To better understand the study’s findings and its potential consequences, UCHealth Today spoke with Dr. Tara Carlisle, a behavioral neurologist and assistant professor of Neurology with the University of Colorado School of Medicine, who practices at the CU Advanced Therapy for Neurodegenerative Disorders (ATND) Clinic, a space within the University of Colorado Neurobehavior and Memory Disorders Clinic at the UCHealth Neurology Clinic – Central Park.  

Carlisle discussed the recent study, the broader impact of genetics on Alzheimer’s disease, and — perhaps most importantly — what people can do to address the risk of the disease proactively. Her conclusion: it’s complicated.  

A recent study suggested that there may be a new genetic form of Alzheimer’s disease. What does the study tell us about Alzheimer’s being genetic? 

The findings were published in Nature Medicine in April and center on the APOE gene. That gene is well-known as a risk factor for developing Alzheimer’s disease, particularly for the 2% to 3% of the general population who have two copies of a specific form of it (or allele), called APOE e4 homozygotes. 

The authors of the study concluded that nearly all people that are APOE e4 homozygotes had abnormally high levels of beta-amyloid — the protein that forms sticky plaque in the brains of people with Alzheimer’s disease – in their cerebrospinal fluid by age 65, and 95% had the biomarkers by age 55. People that are APOE e4 homozygotes also experienced symptoms of Alzheimer’s disease and died as much as a decade earlier than those who did not have APOE e4. 

The study’s conclusion: having two copies of the APOE e4 gene allele should be considered a genetic form of Alzheimer’s disease. That should spur investigations of new prevention strategies and therapies for those individuals, the researchers added.  

Carlisle said the authors of the study offer a “biological definition” of Alzheimer’s disease. That is distinct from defining it in terms of the symptoms that patients exhibit. “The individuals who wrote the article are defining Alzheimer’s disease by the underlying pathology,” meaning the levels of beta-amyloid in people with APOE e4 homozygotes, she said. 

“They are arguing that if you have two copies of the APOE e4 gene, there is a predictable timeline as far as when you will start to develop [cognitive] changes that are consistent with Alzheimer’s disease,” she said.  

Is it significant that the study identifies another genetic form of Alzheimer’s disease? 

That is up for debate, Carlisle said.

“For an individual who has two copies of APOE e4, does that mean that at some time in their lifetime they are going to experience meaningful cognitive changes? Not necessarily,” she said.  

For example, a “good portion” of the study participants were asymptomatic, Carlisle noted.

“How meaningful is it to those individuals, especially if they have something else they might die from before they actually have any symptoms?”  

Other factors complicate the question, she said. Previous studies showed that women with the APOE e4 gene are at significantly higher risk for developing Alzheimer’s disease than men. In addition, dozens of other genetic markers play a role in determining Alzheimer’s disease risk, Carlisle said. 

“Just knowing your APOE e4 status is a tiny piece of the puzzle because there may be so many other genes playing a role,” she said. “It doesn’t help you understand your very specific risk; rather, it is providing some information about the study population in general.”

Environmental factors and prevention measures – more on these later – may also come into play, she added.  

Are there other caveats to the APOE genetic study? 

Yes. Carlisle noted — as did the study authors — that the participants were mostly White Europeans.

“The population was narrow,” she said. “That makes it pretty hard to generalize their findings.” 

Additionally, Carlisle said, people that participate in these types of studies tend to be healthier and more educated than the general population.

“These are also significant risk factors for developing dementia, so it is possible that genetics may play a greater role in this subset of the population,” she said.

When should a person consider genetic testing for Alzheimer’s disease? 

“Right now we do not recommend that anyone who is asymptomatic get testing for their APOE e4 status,” Carlisle said.

She noted that everyone has a roughly 10% risk of getting Alzheimer’s disease during their lifetime.

“So even if you don’t have the APOE e4 gene, you could still develop Alzheimer’s disease because of other genes and lifestyle factors that play a role.”  

Privacy is another concern for people who consider testing before they are symptomatic, Carlisle said. There are measures for protecting individuals from discrimination on the basis of genetics. However, testing information could still get out, and affect their ability to get insurance or their job status, she noted.  

The worry is not hypothetical. The commercial genetic-testing company 23andMe settled a class action lawsuit earlier this summer for an October 2023 data breach that compromised the privacy of nearly 7 million customers. A smaller, but still significant, number of those customers had their genetic and other health data exposed. 

What if I do have cognitive symptoms? Should I then consider genetic testing for Alzheimer’s disease? 

Carlisle advised caution.

“Even if someone does have symptoms, it’s not necessarily going to change how I am going to treat them,” she said. A key question is what a person would do differently if they knew they had the APOE e4 homozygote, other than to make lifestyle modifications that could reduce the 10% risk that everyone has, she added.  

So is there any reason to test for the APOE gene? 

Yes. People who have been diagnosed with mild cognitive impairment or mild dementia due to Alzheimer’s disease and are candidates to receive infusions of the FDA-approved amyloid-targeting drugs Leqembi (lecanemab) – recently available at UCHealth University of Colorado Hospital) – and Kisunla (donanemab) should seriously consider APOE genetic testing. That’s because the drugs increase the risk of amyloid-related imaging abnormalities, or ARIAs, including brain bleeds and swelling, in people with one or two copies of APOE e4. 

“The only [current] indication to do APOE testing from a clinical perspective is if someone is considering anti-amyloid therapy,” Carlisle said.  

What does the genetic testing entail? 

It is a blood test for the APOE alleles alone, with results generally coming back in seven to 10 days, Carlisle said.  

We’ve been talking about risk. But are there genes that we know cause Alzheimer’s disease? 

Yes, but they are responsible for only about 5% of all Alzheimer’s disease cases, Carlisle said. A person who inherits one of these three genetic mutations from their mother or father is “basically guaranteed” to have Alzheimer’s disease at some point, she said, but added “there is some nuance to that.” 

If my genes determine that I will develop Alzheimer’s disease, how can there be ‘nuance?’ 

Each of the three genes have different “penetrance levels,” Carlisle explained. That means, “if you have that mutation, what is the likelihood that you will develop Alzheimer’s disease in your lifetime?” she said.  

For example, one of the three rogue genes, Presenilin (PSEN)1, generally causes symptoms to appear earlier in life than the other two. “Each of these genes have different penetrance rates. And your specific rate may differ from someone else who has a mutation of the same gene,” Carlisle said. And of course, with symptoms often developing later in life, an individual could die of some other cause before the symptoms appear, she added. 

In general, how great a risk is family history for Alzheimer’s disease? 

The Alzheimer’s Association calls family history “a strong risk factor” for the disease, but Carlisle said the number-two culprit is being a woman. Women account for roughly two-thirds of people in the United States with Alzheimer’s disease. One explanation is that women on average live longer than men, but Carlisle said the question is complicated.  

“Some of it is probably because of environmental factors, with men and women having different exposures during their lifetimes,” she said. “There might be a genetic component as well, with genes playing more of a role, perhaps, with women in developing Alzheimer’s disease.” 

In addition, a recent randomized trial of older adults without symptoms of dementia showed that those whose mothers had a history of impaired memory at any age were more likely to have higher levels of beta-amyloid.  

So if my mother had Alzheimer’s disease, how concerned should I be? 

It is important to know if your mother or any other family member suffered cognitive decline, including Alzheimer’s disease. But that background does not determine that you will develop the same problems, Carlisle said. 

“A lot of people come to my clinic and say, ‘Dr. Carlisle, my mother had Alzheimer’s. When am I going to get it?’”, she said.

But for all the reasons mentioned above, the vast majority of people are not fated to develop Alzheimer’s disease. She noted, for example, that the Lancet Commission recently published a report that detailed more than a dozen modifiable risk factors that the authors say could “prevent or delay nearly half of dementia cases.”   

What are preventable risk factors that could prevent or delay dementia? 

They are diverse, Carlisle said, and include improving education, treating hearing loss, addressing depression, building social connections, engaging in cognitively stimulating activities, exercising, avoiding tobacco completely and alcohol to excess, and treating health problems like high blood pressure and obesity. 

“If you have a bunch of risk factors in addition to a genetic profile that increases your risk, you might have your onset of Alzheimer’s disease be even sooner,” she said. “But if you intervene, you might slow down the progression or the onset of symptoms.” 

Are there genetic variants that decrease the risk of developing Alzheimer’s disease? 

Yes. Research shows that people with one or two copies of the APOE e2 gene alelle are far less likely to fall prey to Alzheimer’s. Another rare variant of the APOE gene, known as the Christchurch, was shown to protect the brain against deterioration from Alzheimer’s disease, even in an individual with the PSEN1 mutation. Yet another study has isolated another variant that may protect against Alzheimer’s disease by reducing the buildup of a protein that prevents the body from clearing beta-amyloid deposits from the brain through the bloodstream.  

“The importance is in finding specific mutations and understanding them in more detail so that maybe we can take advantage of whatever it is that makes them more protective, and then possibly apply them to someone else,” Carlisle said. 

Whatever my genetic makeup may be, what are the basics for reducing my risk of Alzheimer’s disease? 

Carlisle pointed to the modifiable risk factors listed by the Lancet Commission, and added that she and her colleagues share with their patients the “Six Pillars of a Brain-Healthy Lifestyle.” These include: 

• Regular exercise: Aim for 150 minutes of aerobic activity a week, as well as strengthening and balance exercises. 

• Healthy diet: Look into the MIND diet, which is a combination of the Mediterranean diet and the heart-healthy DASH diet. 

• Mental stimulation: Keep your mind active with brain teasers, crossword puzzles, reading, and learning new skills, such as taking up a new language, playing an instrument or discovering a new hobby). 

• Quality sleep: Go to bed and get up at the same times every day. Napping is okay in the early afternoon for no more than 45-60 minutes. Get tested for sleep apnea if you snore. 

• Stress management: Practice deep-breathing exercises, look into meditation, and do activities that you enjoy daily. 

• Active social life: Volunteer, join a social group, make a weekly lunch date with friends, get out to movies, museums, parks, and other public places.  

“I joke that it should be the eight pillars, because 1, 2 and 3 should be exercise,” Carlisle said. “Not only has it been shown to maintain cognition, but even in people with a diagnosis of mild cognitive impairment, an exercise program can not only slow it down, but actually lead to improvement.”