Does Alzheimer's disease run in your family? Children of parents with familial Alzheimer's disease (FAD) have a 50% risk of inheriting their parent's mutation and disease. They often find themselves asking - Should I get tested for the genetic mutation?
In this video, we discuss the ins and outs of genetic testing with Genetic Counselor Jill Goldman. Goldman is a genetic counselor at the Center of Excellence for Alzheimer's Disease at the Taub Institute, and a professor of genetic counseling in neurology at Columbia University Medical Center. She specializes in hereditary neurological diseases like FAD, and has also worked with other hereditary diseases such as frontotemporal dementia (FTD) and Huntington's disease.
Goldman has been working as a genetic counselor since 2000, and has authored many papers and book chapters on this topic, including guidelines that all genetic counselors follow for helping families go through genetic testing for Alzheimer's disease.
This interview addresses critical questions for those about to embark on this difficult journey of finding out their genetic status:
How do I know I'm ready to undergo testing?
What do I need to do before contacting a genetic counselor?
What can I expect for the genetic testing process?
This conversation reflects Goldman’s unique perspectives and experiences as shared with us on October 2, 2020. Insights from experts like Goldman help us navigate the unique challenges we face as members of this community.
This transcript has been edited for clarity and readability. For the full interview, watch the video.
LINDSAY: Jill, thank you so much for taking the time to join us today.
GOLDMAN: Thank you for having me.
LINDSAY: There's a lot of confusion when it comes to genetics and Alzheimer's disease. Can you talk about what predictive genetic testing is, and who is eligible for it?
GOLDMAN: There are three different types of family histories that we see [in people who want to undergo genetic testing for Alzheimer’s disease].
The majority of people have sporadic Alzheimer's disease, and it’s usually late onset. It's the first case of Alzheimer's in the family. For someone who has late onset Alzheimer's disease, there is no appropriate genetic testing.
The second group of people have perhaps several cases of Alzheimer's disease in the family. There may be some that are late onset and there may be some that are earlier onset.
This group sees more Alzheimer's disease than you would expect to have, but still not the autosomal dominant family history we see in familial Alzheimer’s families. You don't see it every generation at an early age.
There may be some family members that have siblings or parents or even children with the disease and don't get it themselves. So that's different from the autosomal dominant families.
When you see this family clustering, what you think of is not the three familial Alzheimer’s genes [PSEN1, PSEN2, or APP.]. In all likelihood, we would test someone from that kind of family and not find a mutation in any of those three genes.
Instead, we think of risk genes. The most obvious [of the risk genes] is the APOE gene. This is a gene that everybody has. It comes in three forms: APOE2, APOE3, and APOE4.
We know that APOE4 is associated with a higher risk of Alzheimer's disease.
And there is what is called a dosage effect. If you have two copies of APOE4, you have substantial lifetime risk. But lifetime risk can mean [a person is likely to get the disease at] the age of 85 or even older. If you have one copy [of APOE4], you're at about a three times greater risk than if you have no copies.
Unfortunately there are 6 million people [in the US] that have Alzheimer's, so we're all at risk, whether or not we have [one of two copies of] APOE4. There are plenty of people walking around with APOE4, even two copies, who don't develop Alzheimer's disease, and vice versa. And there are many people who do get it who don't have APOE4.
[The third group is people with a family history of autosomal dominant Alzheimer’s disease. Unlike risk genes,] if you have a mutation in PSEN1, PSEN2, or APP, you will get the disease.
LINDSAY: Why should somebody who has two copies of APOE4 not get genetic testing?
Great question. And we know there are many, many, many other risk genes as well. And some modifier genes that might actually reduce risk, which is what APOE2 does.
When you're in a familial cluster situation [like the second group I mentioned], you would really have to have what is being developed now, which is called a polygenic risk score, where you're testing all known associated genes. And then, you have to throw in environmental factors that might influence the genes. So it's a much more complicated situation.
LINDSAY: So predictive genetic testing is really only meant for families with those autosomal dominant mutations in their family. Correct?
GOLDMAN: That is correct. Although there are many people who want to be tested for APOE4, [the field does not currently recommend doing predictive testing for it].
LINDSAY: There are a lot of issues related to mortality, psychology and family dynamics built into finding out whether someone carries an FAD mutation.
What are some advantages or reasons why somebody would pursue genetic testing?
GOLDMAN: [The reasons are] ever changing. What's making it ever changing is our clinical trials. With the availability of clinical trials, more people will probably opt to test than already do. When we look at all of these fatal autosomal dominant diseases, whether it be FAD or Huntington's disease, of all the people who are at 50% risk because one of their parents has it, only about 20% of people go see a genetic counselor. And some of those people actually decide not to test after thinking about it [and meeting with a counselor].
The main reasons that people DO decide to test are:
Reproductive options.
Life planning. ”Do I want to retire early?” “Do I want to go to medical school and then not be able to practice for very long if I carry this gene?” Things like that.
Removing uncertainty. "I can't deal with this uncertainty anymore” or” I'm going to be better off knowing and being able to plan than not knowing and fearing it every day.”
Candidacy for clinical trials, which is relevant now because of the gantenerumab open label extension by DIAN. [Editor’s Note: The Dominantly Inherited Alzheimer Network (DIAN) is an international research effort focused on FAD, also knows as DIAD (Dominantly Inherited Alzheimer disease).]
[Editor’s Note: Since this interview in Oct 2020, the FDA has approved new treatments for Alzheimer’s. These new treatments are another reason some people get tested. Learn more about the risks and benefits of genetic testing in our guide to genetic testing.]
LINDSAY: Why would someone choose not to know?
GOLDMAN: Many reasons. The greatest proportion of people who don't want to know think that they can't cope with the result if it's positive. [Editor’s note: Testing positive means finding out you do carry a mutation].
There are plenty of people who say, “I don't want to think about this for the rest of my life. We're all going to die of something. I could get hit by a bus tomorrow or get cancer or have a heart attack or whatever before I get Alzheimer's disease. Why should I know?” You know, the fatalistic outlook and that's fine.
“There’s no right or wrong in any of this. This is a very personal decision”
There's no right or wrong in any of this. This is a very personal decision. Looking at it from a genetic counseling point of view, we want the best outcome for folks. We don't want people testing if they think that they can't cope or we think that they can't cope, so we strongly suggest that someone has a psychiatric evaluation before going through this. That may be a therapist that they have been involved with for a long time, or it may be a therapist at the center that's doing the testing.
We know from the literature that the chances of a bad outcome are greater when someone has had a prior history of depression or significant anxiety. We also see that people who haven't spent a lot of time thinking about the impact and ramifications of testing may not do well.
Genetic counseling is what I call anticipatory guidance, talking someone through all the possible things that might come up for them post-results.
LINDSAY: Some people who know they want to get tested, and others know they don’t. But what about the people who are in between? One day they may think, ‘I want to know.’ Another day they think, ‘I don't want to know.’ What would you tell somebody who's having those thoughts? Is there any sort of criteria that you notice in people who can’t cope?
GOLDMAN: It's not so much that they have a history of anxiety and depression, as that they haven't dealt with it. Certainly, if you grow up in a family with these kinds of diseases, it is highly probable that people have experienced a lot of stress. As a result significant depression and anxiety would not be unusual.
If they are facing that, and they are dealing with what the depression and anxiety is all about, and learning how to cope with those feelings, they'll probably do well.
What we don't want is someone with active depression and anxiety without a support system, without a therapist helping them, without medication, if that's necessary. We don't want them diving in. It would be better that they just take their time until they're more sure that this is the right thing for them. People have to take their time. They can't make fast decisions.
It's not like you should go into your doctor's office and say, "I want this test.” Some doctors will do it and then they're stuck. Because there's going to be a result there.
So I would say, really deal with your issues first. And when you think that you are…. I can't give a percentage, but let's say 90 to 95% sure you want to do it… I mean, everybody you know is going to vacillate somewhat. Even after you get your result, you're going to go, “why did I do that?” But if you can be a lot more sure than unsure, the outcome is going to be better.
LINDSAY: Talking about outcomes, what are the psychological impacts of learning your genetic status? How do people cope?
GOLDMAN: Most of the literature says that people have a period of time where they have a psychological impact of the result. And then, over time–a year is probably what the literature says–they go back to baseline, based on taking the psychological assessments, before, right after, and, six months to a year [after the result].
Obviously that's going to differ between different people.
I think it also depends on your reason for testing. For many people who are trying to make decisions about IVF with PGT [in-vitro fertilization with preimplantation genetic testing], having that result allows them to move on. And that's a good thing.
Another significant part of a good outcome is having a support system, whether it be your family or a partner or really good friends who are around you. That's really important.
LINDSAY: So, let's say somebody decides, “Okay, I'm ready to pursue genetic testing.” What should they set into place before they contact a genetic counselor?
GOLDMAN: Everybody should realize that you can contact a genetic counselor [and decide not to get tested]. You can come in, and have a consultation with a genetic counselor, and still decide not to go forward. I think that's really, really important. It should be in your control. You call the shots as to how soon you want to do it, or whether you want to wait. I have many folders with results in them that have not been returned because the person has decided that they weren't ready. And that's just fine.
“ I have many folders with results in them that have not been returned because the person has decided that they weren’t ready. And that’s just fine. ”
The one thing that people should think about, before they get a genetic result is whether or not they want to obtain life insurance and long term care insurance.
There is a law called GINA which is the Genetic Information Nondiscrimination Act, and that protects you against discrimination for health insurance and in the workplace. But it doesn't cover life insurance or long term care or disability. Veterans aren't covered by GINA, and there's a couple other situations that aren't covered. [Editor’s Note: Learn more about GINA]
It is hard for young people to think about obtaining all that insurance. It's expensive. And we don't know for a fact how much discrimination there really is. But if you're applying [for insurance] and someone asks you, ‘what's your family history?’ You have to own up to your family history.
You can try to maneuver. You can say, “Mom has a neurological condition,” But if they ask what, you have to say Alzheimer's disease. And if someone says, “Have you ever had genetic testing?” You can't lie. If you already have your test result, that's insurance fraud, and theoretically, you could lose whatever money you put into it. [Getting these insurances] isn't required for genetic testing, but it's something that we warn everybody about.
[Ultimately people] choose what they want to do. Many people will decide long term care insurance is going to be too expensive in the long run. They might decide, I can't afford a good enough policy, so I'm going to establish my own separate bank account and contribute to it. And that's going to be my long term care insurance.
Learn more about long term care insurance from our interview with…
LINDSAY: Can you describe what the genetic testing process looks like (like how many sessions there are, the length in between finding out your results, and when you do the swab or have your blood taken)?
GOLDMAN: Centers differ tremendously. Most centers will have you see a genetic counselor. The session will be about an hour.
Then, you will see a doctor, a neurologist or a psychiatrist or the combination. Each center is a little bit different in what they do. Some people will see a geneticist rather than a neurologist. But that person is going to be the ordering physician, because genetic counselors can't sign off for their own tests. They can coordinate it, but there has to be an ordering physician.
There are several labs in the US that do this highly specialized testing. An individual can't just go to LabCorp or Quest and say, I want this test. It is a specialized test.
Different labs differ in how long it takes to get results. It certainly is much faster now than it used to be. I usually tell people about three weeks. And [when the results are ready] then they would come back in, with their support person, and get face-to-face results. Nowadays [it’s also possible to do this] on zoom in most places, but it is face to face without masks on zoom.
LINDSAY: Is there anything you can say related to the cost of genetic testing that people can expect?
GOLDMAN: Cost has come down tremendously. Even a few years ago, some labs were doing full sequencing of each gene. And that was very, very expensive.
Nowadays, the labs are doing next-generation sequencing. So they're basically testing the entire exome, but only analyzing and reporting specific genes. That's done all at once. So it depends on what is known about the genetic cause in the family.
LINDSAY: What does genetic testing look like if someone has their parent's DNA, and is it different if they don't have it?
GOLDMAN: When they don't have it–let's just say the parent has had an autopsy, and we know it is Alzheimer's disease. That's one scenario. You would only test for the Alzheimer's genes under that scenario.
But sometimes people have a family history of dementia, and we don't know exactly what kind of dementia, because they can overlap. So if we don't know whether it is Alzheimer's disease or frontotemporal dementia, we would do a larger panel. For most labs, it doesn't matter how many genes are on the panel, it's the same price.
The big difference is the more genes that you test, the more likely you are to get what is called a variant of unknown significance - a “VUS”.
When you don't know what the exact mutation is in the family, you can do a large panel. There are several possible outcomes.
You can find nothing. That would be a negative result.
You could get a definite positive, a known mutation in one of the genes.
Or, you could get one or more of these variants of unknown significance, which basically means that a change or changes in the DNA were found that have either not been reported or, have not been proven to be associated with Alzheimer's disease or whatever the disease is.
That’s a VUS. If you get a VUS, you're in the same boat you were before you tested it. It's an uncertain result.
Now, over the next few years, that result may change. The lab, with additional information in their databases, may go back, and say that this is actually a benign change or it is definitely a pathogenic [disease-causing] change. So you may get more information in the future.
LINDSAY: So, these larger panels, I've heard, can cost $1600 to $2000. Is that about right?
GOLDMAN: No, it is not. Labs are different, but there is no reason in the world at this point that you can't get a test for $250, no matter how many genes are on that panel. And that does not matter if it is a blood test or a saliva test.
LINDSAY: So cost is not as much of a barrier to genetic testing like it used to be.
GOLDMAN: And that's out of pocket, because people who are doing predictive testing wouldn't be covered by their insurance anyway. But, because of possible discrimination issues, it’s probably better, if they can pay out of pocket, to go that route, right?
LINDSAY: Yes. Because then that information isn't in their medical record, and the insurance company can't use it later on.
GOLDMAN: Yes, and that's a question that people should ask their physician or their genetic counselor prior to testing, because some places will do anonymous testing and other places won't. Some places put everything into the electronic medical record, other places keep shadow charts and don't.
LINDSAY: So if somebody is very worried about this issue, they could pursue anonymous testing, or make sure that the counselors and the neurologists use paper charting instead of putting everything into an electronic database.
GOLDMAN: Correct. Right now, the problem with anonymous testing is that you can't prove it's you. So if you were doing testing in order to do IVF, you're going to have to get retested.
LINDSAY: That's good to know. And also if you're symptomatic, you probably can't do it anonymously. You would need to do it under your name, so that you get the right Social Security benefits.
GOLDMAN: Exactly.
LINDSAY: A lot of families struggle with the best way to communicate this sort of information to other family members. What do you tell your children? What age is the best? It would be great to hear any recommendations for having those difficult conversations.
GOLDMAN: I think a lot of it depends on how old the person being tested is, and how old their children are. There are all kinds of ethical issues that come up when you're dealing with families.
The first that comes to mind is: what if you want to test because you want kids, and you want to know whether you need to do IVF. And the family history is that your aunt has a known mutation, but your father doesn't want to test. And then you test, and you're positive. So you have revealed both your status and your father's status. That's really, really hard. And that's something that certainly would be discussed in a genetic counseling session prior to testing.
“I strongly encourage people to have a hypothetical conversation with their family prior to their testing. ”
I strongly encourage people to have a hypothetical conversation with their family prior to their testing. You know, “I am thinking about doing this. If I do, I'd like to share the results. But if you don't want them, I want to respect your decision.” So it is on the table before that piece of paper is in your hands.
Some people go, “No, you don't know my children. My son is extremely anxious and I don't want to raise his anxiety anymore unless I absolutely have to.” And, they DO know their children a lot better than I do. I may never have met these children.
So, I think it's important to think about, but everybody does know their situation best.
[INSERT LINK TO TALKING TO KIDS]
In terms of telling younger children, I don't think it's necessary. Younger children aren't going to understand, they don't have to act on anything when you know they are young. I don't know if there is a right age, but certainly if the parent is sick, there will be questions.
And you're not going to tell an eight-year-old because they're going to worry so much, but you might tell them a little bit, you might just start introducing the whole concept of inheritance. You know, mom has this disease called Alzheimer's disease. And, granddad had it too.
Sooner or later you're going to get the question: what about me? Am I going to get it? And you certainly don't have to go into the full genetics there. But, you might say, we don't know, some people have diseases in their family, and not everybody gets it. You don't ignore the question, but you keep on adding at age appropriate levels.
I think it's almost harder with the older, young adults who haven't been told and then are smacked in the face with it. When they're in a relationship and the parent finally feels that they have to know. There can be a lot of anger, why wasn't I included in this? Don't you think, I'm old enough and competent enough to be able to deal with it. So I think you have to look at that as well.
LINDSAY: I like your idea of age appropriateness, so it doesn't feel like that smack in the face. Once children get to that reproductive age, it could be really important to disclose that information.
Along those lines, other people also struggle with telling their extended family. This could be family that doesn't know about the risk. Is it your responsibility then, with this newfound knowledge, to share that with them? And the best way to go about it?
GOLDMAN: That's a really good and very difficult question. Families are families. There are many families that are estranged, and they don't want to go near the part of the family they don't talk to.
Certainly ethically, it is important information. And, in a way, people have the right to know what they're at risk for.
That doesn't mean that someone has to call a relative up and say, I've just been diagnosed with this, I have this mutation.
This is where genetic counselors can really help. One of the ways they can help is to compose a letter that is a little bit more generic.
“We're writing this because we think that this is important information that you might want to know. Someone in the family has been diagnosed. And we also want you to know about this clinical trial. If you're interested, please contact…”
So that's a little bit less personal, but it's still getting the information across.
You send it, but you and the genetic counselor compose it together.
LINDSAY: I didn't know that you could ask genetic counselors to do that for you. That's great.
With the advent of commercial DNA sequencing kits like 23 and Me and Ancestry, some people may wonder, why should I even go to a genetic counselor?
From your perspective, if someone is going to pursue predictive genetic testing, why go to a trained genetic counselor versus doing it on your own with one of these commercial kits?
GOLDMAN: Number one, you can't do it on your own. None of the companies have approval to test for dominantly inherited Alzheimer's disease or Huntington's disease.
The only way you could do it is if you do a commercial test, and then ask for the raw data.
Learn more about the risks of using direct-to-consumer genetic tests to find FAD genetic mutations.
And if you read the small print, you will read that they cannot take responsibility for what that data says, except for the traits that they release on their regular testing results, which have been confirmed in a federally approved lab. When you get your raw data, what people do is they stick that data into another website that analyzes the data and spits out the results.
There was an article in the New York Times, I think in 2018, about a young man who did this, and found out that he had a PSEN1 mutation with no family history at all. His parents were in their 60s and just fine. He panicked, and tried to get his doctor to test him in a lab.
His doctor thought the whole thing was just ridiculous, and wouldn't do it. So, he sent a second sample to Ancestry.com, and he waited till he got that result, and that result was different. He didn't have the PSEN1 mutation, and he liked that result better. He sent a third sample to 23 and me, and got the same result he got the first time, which is pretty predictable, because if they have something wrong with what is generating their raw data, then it's going to be wrong all the time.
Eventually, he got clinically tested, and he was negative, and this just shows the problem with these companies.
You're not getting the whole story, and you really have to read between the lines. If you go to a genetic counselor, you're going to know what you're testing for, and you're going to be able to really think of the ins and outs of that testing, and the impact of that testing on you, on your partner, on your family, in all the ways that we described before, which you can't get on your own.
LINDSAY: Jill, thank you so much for again taking time to talk with us about this really important issue for our community. You made some really great points and brought a lot of insight. So thank you.
GOLDMAN: You are very welcome.
You can learn more from Jill Goldman on the topic of genetic testing and FAD if you read her paper entitled “Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors.”