Recent advances in the genetics of Alzheimer’s disease

Recent advances in the genetics of Alzheimer’s disease
Alzheimer’s disease is a progressive brain disease that interferes with a person’s memory, thinking, and behavior. The greatest risk factor is age, but genetics can impact the chance of disease development and age of onset. Whether you have a family member with Alzheimer’s disease or you’re curious about what the latest science has to offer, let’s understand what’s currently possible to detect through genetic testing.
Written by Christina Ren, Certified Genetic Counselor 
Orchid offers advanced genetic testing for couples who want their child to have the best shot of a healthy life. “Genetics for Humans” is where we unpack how genetics impacts our everyday lives and the latest tools to help you build a healthier family. 

What is Alzheimer’s disease and how does it impact individuals? 

Considered the most common form of dementia, Alzheimer’s disease affects 1 in 10 individuals. It’s a neurodegenerative brain disease — the brain shrinks in size and symptoms worsen over time. 

Alzheimer’s disease has a heavy emotional cost to both affected individuals and their caregivers. In Joanne Koenig Coste’s book Learning to Speak Alzheimer's, she calls it a "disease of the emotions” — describing many of the feelings that arise as a direct consequence of individuals struggling through their cognitive difficulties. Here is a collection of personal stories from family members who watched their loved ones experience signs of dementia. 

Does Alzheimer’s disease run in families? 

Many people with a family history of Alzheimer’s disease (AD) naturally worry about their own risk of developing it, too. 

Bottomline is that genetics can play a strong role in Alzheimer’s disease, especially for early-onset Alzheimer's disease (before age 60). Studies estimate that late-onset Alzheimer’s disease is 58 to 79% heritable and early-onset AD can be over 90% heritable. 
What this translates into is first-degree relatives (children, full siblings) of an individual with Alzheimer’s disease have a 2 to 4 fold increased chance of developing AD compared to the general population. So, over the course of these first-degree relatives’ lifetime, the chance of developing AD is around 15 to 39%. 

Is there a single genetic cause for Alzheimer’s disease?

Most of the time, no. There is no single “Alzheimer’s Disease Gene” like the Huntington’s disease gene that explains it all.  

Genes that can cause Alzheimer’s disease, but are rare

In the past, three genes have been identified to cause a small portion of Alzheimer’s disease cases: APP, PSEN1, PSEN2. These are considered “high penetrance genes”, meaning if you have a mutation in one of those genes, you have over a 95% chance of developing AD in your lifetime. 

But mutations in these three genes are rare. They explain only 1-5% of all AD cases. This means the vast majority of people with Alzheimer’s disease don’t have a causative gene mutation. So, if you just did genetic testing looking for a mutation in these 3 genes, most of the time, you wouldn’t find anything meaningful to you.

One risk factor gene, which isn’t predictive enough alone 

The other gene that attracts a lot of attention is Apolipoprotein E (APOE). This is what direct-to-consumer DNA tests often offer as a genetic test for Alzheimer’s disease. People with at least one copy of the ε4 variant have an increased risk of developing late-onset AD. 

The reason why many clinicians discourage testing for APOE genotype is because that alone is not predictive enough. Up to 75% of people with one copy of ɛ4 (the high-risk variant) do not develop AD during their life, and about one-half of people with AD do not carry the high-risk ɛ4 variant. This means you can have normal (or even protective) versions of the APOE gene (ɛ3 or ɛ2) and still develop AD. 

So if 3 genes only explain a very small portion of Alzheimer’s disease cases and APOE genotyping isn’t predictive enough, what’s beyond that? It turns out there are even more genes involved. What’s become increasingly apparent for the vast majority of people with Alzheimer’s disease is that there is no single genetic cause. The reality is more complex. To properly measure genetic predisposition to AD, you have to assess the whole landscape by looking at many genes and genetic markers combined.  

Is there a genetic test for Alzheimer’s disease?

Yes, there is now a way to measure your genetic predisposition to Alzheimer’s disease. This is different from a diagnosis, however. Genetic screening can tell you if you are more or less likely to develop Alzheimer’s disease than the average person based on your genetic background. 

This is done by comparing the genetic makeup of tens of thousands of individuals diagnosed with Alzheimer’s disease (“cases”) with individuals without AD (“controls”). Using data from over 70,000 individuals, genetic risk scoring for Alzheimer’s disease can now predict both the chance of developing Alzheimer’s and the estimated age of onset. Individuals with elevated genetic risk are more likely to develop Alzheimer’s at an earlier age, even comparing among individuals with normal APOE genotype (ɛ3/ɛ3). In this study, for a person who had the normal APOE genotype but had a high genetic risk score (above 90th percentile), the expected age of develop AD is age 84. But if that same person had a low genetic risk score (below 10th percentile), age of onset is over 10 years later.

With advanced genetic testing like what we do here at Orchid, you can get a sense of your genetic predisposition to Alzheimer’s disease and remove some of the guesswork on what you can pass on to your future children. 

What actions can I take based on the information from a genetic test for Alzheimer’s disease?

If you or your future child has an elevated genetic risk for Alzheimer’s disease, the risk of developing AD at some point in life can be up to 5 times higher than in the general population. 

The useful thing about your results is that if you identify certain genetic vulnerabilities that can impact you or your future children, you can potentially do something about it and mitigate these risks. Ways you can act on your results include:

  • Offset genetic risks with healthy lifestyle choices. Genetics is just one component of your chances of getting Alzheimer’s disease. This means you can significantly lower your overall risk with personal lifestyle choices, which is especially important if you have a higher genetic risk. Researchers have identified 12 risk factors that contribute to Alzheimer’s disease development, some of which include smoking, reduced social interaction, and physical inactivity. The hopeful picture is that about 40% of cases of Alzheimer’s disease can be potentially prevented by eliminating these modifiable risk factors.  
  • Embryo screening to reduce your child’s potential genetic risks. Embryo screening allows you to quantify each embryo’s genetic risk for Alzheimer’s disease and other common conditions. This allows you to prioritize the transfer of embryos with the lowest genetic risk and thus reduce your future child’s genetic risks.  

Key takeaways 

  • Alzheimer’s disease is a common condition that can disrupt the daily lives of affected individuals and their caretakers.  
  • Past family studies have shown that genetics play an important role in the chance of developing Alzheimer’s disease.
  • Advanced genetic testing can now see if this genetic component to Alzheimer’s disease can be quantified for you and your family. 
Resources 


Orchid offers advanced genetic testing for couples planning on building their family. We use advanced tools and smart, caring humans to help you give your future children the best shot of a healthy life. Conceive with greater confidence and peace of mind


1/7/2021
Genetics
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