{"id":77948,"date":"2024-09-19T11:18:32","date_gmt":"2024-09-19T17:18:32","guid":{"rendered":"https:\/\/www.uchealth.org\/today\/?p=77948"},"modified":"2024-10-18T09:48:55","modified_gmt":"2024-10-18T15:48:55","slug":"alzheimers-disease-and-genetics-a-complicated-relationship","status":"publish","type":"post","link":"https:\/\/www.uchealth.org\/today\/alzheimers-disease-and-genetics-a-complicated-relationship\/","title":{"rendered":"Alzheimer\u2019s disease and genetics: A complicated relationship\u00a0\u00a0"},"content":{"rendered":"
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\"elderly
Mental stimulation, along with exercise, a healthy diet and quality sleep all can help prevent Alzheimer’s. What about the genetic risks? A new study provides some answers, but also raises new questions. Photo: Getty Images.<\/figcaption><\/figure>\n

Age is the greatest risk for Alzheimer\u2019s disease, and Alzheimer’s risk <\/span>increases in people steadily<\/span><\/a> from the age of 65 upward. That hard fact translates to 7 million people who suffer from the neurodegenerative disease and the expectation that <\/span>the number could nearly double by 2050<\/span><\/a>.<\/span>\u00a0<\/span><\/p>\n

The statistics may also lead some to believe that Alzheimer\u2019s disease is an inevitable outcome of aging. That fatalistic view might be strengthened by research that examines the role genetics plays in Alzheimer\u2019s disease. One recent example is a study whose authors announced that they had established a <\/span>new genetic form of Alzheimer\u2019s disease<\/span><\/a>.

Keep up to date with the latest news on Alzheimer’s disease.<\/a><\/div><\/span><\/p>\n

To better understand the study\u2019s findings and its potential consequences, UCHealth Today spoke with <\/span>Dr. Tara Carlisle<\/span><\/a>, 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 <\/span>University of Colorado Neurobehavior and Memory Disorders Clinic<\/span><\/a> at the <\/span>UCHealth Neurology Clinic \u2013 Central Park<\/span><\/a>.\u00a0<\/span>\u00a0<\/span><\/p>\n

Carlisle discussed the recent study, the broader impact of genetics on Alzheimer\u2019s disease, and \u2014 perhaps most importantly \u2014 what people can do to address the risk of the disease proactively. Her conclusion: it\u2019s complicated. <\/span>\u00a0<\/span><\/p>\n

A recent study suggested that there may be a new genetic form of Alzheimer\u2019s disease. What does the study tell us about Alzheimer’s being genetic?<\/span><\/b>\u00a0<\/span><\/h2>\n

The findings were published in <\/span>Nature Medicine<\/span><\/i><\/a> in April and center on the <\/span>APOE gene<\/span><\/a>. That gene is well-known as a risk factor for developing Alzheimer\u2019s disease, particularly for the 2% to 3% of the general population who have two copies of a specific form of it (or <\/span>allele<\/span><\/a>), called <\/span>APOE <\/span>e<\/span>4 homozygotes<\/span>.\u00a0<\/span><\/p>\n

\"Dr.
Dr. Tara Carlisle, behavioral neurologist with the CU Advanced Therapy for Neurodegenerative Disorders (ATND) Clinic, says genetics are just one of many factors that affect the presence and progression of Alzheimer\u2019s disease. Photo by the University of Colorado.<\/figcaption><\/figure>\n

The authors of the study concluded that nearly all people that are APOE <\/span>e<\/span>4 homozygotes had abnormally high levels of <\/span>beta-amyloid<\/span> \u2014 the protein that forms sticky plaque in the brains of people with Alzheimer\u2019s disease \u2013 in their cerebrospinal fluid by age 65, and 95% had the biomarkers by age 55. People that are APOE <\/span>e<\/span>4 homozygotes also experienced symptoms of Alzheimer\u2019s disease and died as much as a decade earlier than those who did not have APOE <\/span>e<\/span>4.<\/span>\u00a0<\/span><\/p>\n

The study\u2019s conclusion: having two copies of the APOE <\/span>e<\/span>4 gene allele should be considered a genetic form of Alzheimer\u2019s disease. That should spur investigations of new prevention strategies and therapies for those individuals, the researchers added.\u00a0<\/span>\u00a0<\/span><\/p>\n

Carlisle said the authors of the study offer a \u201cbiological definition\u201d of Alzheimer\u2019s disease. That is distinct from defining it in terms of the symptoms that patients exhibit. \u201cThe individuals who wrote the article are defining Alzheimer\u2019s disease by the underlying pathology,\u201d meaning the levels of beta-amyloid in people with APOE <\/span>e<\/span>4 homozygotes, she said.<\/span>\u00a0<\/span><\/p>\n

\u201cThey are arguing that if you have two copies of the APOE <\/span>e<\/span>4 gene, there is a predictable timeline as far as when you will start to develop [cognitive] changes that are consistent with Alzheimer\u2019s disease,\u201d she said.\u00a0<\/span>\u00a0<\/span><\/p>\n

Is it significant that the study identifies another genetic form of Alzheimer’s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

That is up for debate, Carlisle said. <\/span><\/p>\n

\u201cFor an individual who has two copies of APOE <\/span>e<\/span>4, does that mean that at some time in their lifetime they are going to experience meaningful cognitive changes? Not necessarily,\u201d she said.\u00a0<\/span>\u00a0<\/span><\/p>\n

For example, a \u201cgood portion\u201d of the study participants were asymptomatic, Carlisle noted.<\/span><\/p>\n

\u201cHow meaningful is it to those individuals, especially if they have something else they might die from before they actually have any symptoms?\u201d\u00a0<\/span>\u00a0<\/span><\/p>\n

Other factors complicate the question, she said. Previous studies showed that women with the APOE <\/span>e<\/span>4 gene are at <\/span>significantly higher risk<\/span><\/a> for developing Alzheimer\u2019s disease than men. In addition, <\/span>dozens of other genetic markers<\/span><\/a> play a role in determining Alzheimer\u2019s disease risk, Carlisle said.<\/span>\u00a0<\/span><\/p>\n

\u201cJust knowing your APOE <\/span>e<\/span>4 status is a tiny piece of the puzzle because there may be so many other genes playing a role,\u201d she said. \u201cIt doesn\u2019t help you understand your very specific risk; rather, it is providing some information about the study population in general.\u201d<\/span><\/p>\n

Environmental factors and prevention measures \u2013 more on these later \u2013 may also come into play, she added.\u00a0<\/span>\u00a0<\/span><\/p>\n

Are there other caveats to the APOE genetic study?<\/span><\/b>\u00a0<\/span><\/h2>\n

Yes. Carlisle noted \u2014 <\/span>as did the study authors<\/span><\/a> \u2014 that the participants were mostly White Europeans. <\/span><\/p>\n

\u201cThe population was narrow,\u201d she said. \u201cThat makes it pretty hard to generalize their findings.\u201d<\/span>\u00a0<\/span><\/p>\n

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

\u201cThese 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,\u201d she said.<\/p>\n

When should a person consider genetic testing for Alzheimer\u2019s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

\u201cRight now we do not recommend that anyone who is asymptomatic get testing for their APOE e4 status,\u201d Carlisle said.<\/p>\n

She noted that everyone has a roughly 10% risk of getting Alzheimer\u2019s disease during their lifetime. \u201cSo even if you don\u2019t have the APOE e4 gene, you could still develop Alzheimer\u2019s disease because of other genes and lifestyle factors that play a role.\u201d<\/p>\n

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, there are exceptions to these protections, she noted.<\/p>\n

In addition, 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.<\/p>\n

\u201cWhen considering any type of genetic testing, a visit with a medical provider who specializes in genetics is recommended. Genetic testing that can be ordered at home is not the same as genetic testing ordered by a doctor or genetic counselor in terms of privacy, accuracy, and comprehensiveness,\u201d Carlisle said.<\/p>\n

What if I do have cognitive symptoms? Should I then consider genetic testing for Alzheimer’s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

Carlisle advised caution. <\/span><\/p>\n

\u201cEven if someone does have symptoms, it\u2019s not necessarily going to change how I am going to treat them,\u201d she said. A key question is what a person would do differently if they knew they had the APOE <\/span>e<\/span>4 homozygote, other than to make lifestyle modifications that could reduce the 10% risk that everyone has, she added.\u00a0<\/span>\u00a0<\/span><\/p>\n

So is there any reason to test for the APOE gene?<\/span><\/b>\u00a0<\/span><\/h2>\n

Yes. People who have been diagnosed with mild cognitive impairment or mild dementia due to Alzheimer\u2019s disease and are candidates to receive infusions of the FDA-approved amyloid-targeting drugs Leqembi (lecanemab) \u2013 <\/span>recently available at UCHealth University of Colorado Hospital<\/span><\/a>) \u2013 and <\/span>Kisunla (donanemab)<\/span><\/a> should seriously consider APOE genetic testing. That\u2019s because the drugs increase the risk of <\/span>amyloid-related imaging abnormalities<\/span><\/a>, or ARIAs, including brain bleeds and swelling, in people with one or two copies of APOE <\/span>e<\/span>4.<\/span>\u00a0<\/span><\/p>\n

\u201cThe only [current] indication to do APOE testing from a clinical perspective is if someone is considering anti-amyloid therapy,\u201d Carlisle said.\u00a0<\/span>\u00a0<\/span><\/p>\n

What does the genetic testing entail?<\/span><\/b>\u00a0<\/span><\/h2>\n

It is a blood test for the APOE alleles alone, with results generally coming back in seven to 10 days, Carlisle said.\u00a0<\/span>\u00a0<\/span><\/p>\n

We\u2019ve been talking about risk. But are there genes that we know cause Alzheimer\u2019s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

Yes, but they are responsible for only about 5% of all Alzheimer\u2019s disease cases, Carlisle said. A person who inherits one of <\/span>these three genetic mutations<\/span> from their mother or father is \u201cbasically guaranteed\u201d to have Alzheimer\u2019s disease at some point, she said, but added \u201cthere is some nuance to that.\u201d<\/span>\u00a0<\/span><\/p>\n

If my genes determine that I will develop Alzheimer\u2019s disease, how can there be ‘nuance?’<\/span><\/b>\u00a0<\/span><\/h2>\n

Each of the three genes have different \u201c<\/span>penetrance levels<\/span>,\u201d Carlisle explained. That means, \u201cif you have that mutation, what is the likelihood that you will develop Alzheimer\u2019s disease in your lifetime?\u201d she said.\u00a0<\/span>\u00a0<\/span><\/p>\n

For example, one of the three rogue genes, Presenilin (PSEN)1, <\/span>generally causes symptoms to appear earlier in life<\/span> than the other two. \u201cEach of these genes have different penetrance rates. And your specific rate may differ from someone else who has a mutation of the same gene,\u201d 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.<\/span>\u00a0<\/span><\/p>\n

In general, how great a risk is family history for Alzheimer\u2019s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

The Alzheimer\u2019s Association<\/span> calls family history \u201ca strong risk factor\u201d for the disease, but Carlisle said the number-two culprit is being a woman. Women account for <\/span>roughly two-thirds<\/span><\/a> of people in the United States with Alzheimer\u2019s disease. One explanation is that women on average live longer than men, but Carlisle said the question is complicated.\u00a0<\/span>\u00a0<\/span><\/p>\n

\u201cSome of it is probably because of environmental factors, with men and women having different exposures during their lifetimes,\u201d she said. \u201cThere might be a genetic component as well, with genes playing more of a role, perhaps, with women in developing Alzheimer\u2019s disease.\u201d<\/span>\u00a0<\/span><\/p>\n

In addition, a <\/span>recent randomized trial<\/span><\/a> 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.\u00a0<\/span>\u00a0<\/span><\/p>\n

So if my mother had Alzheimer\u2019s disease, how concerned should I be?<\/span><\/b>\u00a0<\/span><\/h2>\n

It is important to know if your mother or any other family member suffered cognitive decline, including Alzheimer\u2019s disease. But that background does not determine that you will develop the same problems, Carlisle said.<\/span>\u00a0<\/span><\/p>\n

\u201cA lot of people come to my clinic and say, \u2018Dr. Carlisle, my mother had Alzheimer\u2019s. When am I going to get it?\u2019\u201d, she said. <\/span><\/p>\n

But for all the reasons mentioned above, the vast majority of people are not fated to develop Alzheimer\u2019s disease. She noted, for example, that the <\/span>Lancet Commission recently published a report<\/span><\/a> that detailed more than a <\/span>dozen modifiable risk factors<\/span><\/a> that the authors say could \u201cprevent or delay nearly half of dementia cases.\u201d\u00a0\u00a0<\/span>\u00a0<\/span><\/p>\n

What are preventable risk factors that could prevent or delay dementia?<\/span><\/b>\u00a0<\/span><\/h2>\n

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.<\/span>\u00a0<\/span><\/p>\n

\u201cIf you have a bunch of risk factors in addition to a genetic profile that increases your risk, you might have your onset of Alzheimer\u2019s disease be even sooner,\u201d she said. \u201cBut if you intervene, you might slow down the progression or the onset of symptoms.\u201d<\/span>\u00a0<\/span><\/p>\n

Are there genetic variants that <\/span><\/b>decrease<\/span><\/i><\/b> the risk of developing Alzheimer\u2019s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

Yes. Research shows that people with one or two copies of the APOE <\/span>e<\/span>2 gene alelle are <\/span>far less likely<\/span><\/a> to fall prey to Alzheimer\u2019s. Another rare variant of the APOE gene, known as the <\/span>Christchurch<\/span><\/a>, was shown to protect the brain against deterioration from Alzheimer\u2019s disease, even in an individual with the PSEN1 mutation. <\/span>Yet another study<\/span><\/a> has isolated another variant that may protect against Alzheimer\u2019s disease by reducing the buildup of a protein that prevents the body from clearing beta-amyloid deposits from the brain through the bloodstream.\u00a0<\/span>\u00a0<\/span><\/p>\n

\u201cThe 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,\u201d Carlisle said.<\/span>\u00a0<\/span><\/p>\n

Whatever my genetic makeup may be, what are the basics for reducing my risk of Alzheimer\u2019s disease?<\/span><\/b>\u00a0<\/span><\/h2>\n

Carlisle pointed to the modifiable risk factors listed by the Lancet Commission, and added that she and her colleagues share with their patients the \u201cSix Pillars of a Brain-Healthy Lifestyle.\u201d These include:<\/span>\u00a0<\/span><\/p>\n