Genetic Testing Recommendations in Alzheimer Disease

Jeffrey L. Cummings, MD, ScD: Elaine, I’d like to turn toward genetic testing that’s being discussed more and more as we think about precision medicine across diagnostic categories. What do you say about the role of genetic testing in a diagnosis of Alzheimer disease?

Elaine R. Peskind, MD: I think with respect to precision medicine, we’re way behind genetic and genomic testing for cancer, where certain gene profiles actually predict response to treatment. At this point we’re not there yet in Alzheimer disease. But I want to say that there are families in which Alzheimer disease is a genetic disease. And it is transmitted by what we call an autosomal dominant pattern; roughly half the people in every generation are affected. And if you have an affected parent, your risk is 50%.

Genes that we have identified that cause Alzheimer, mutations that cause Alzheimer disease, are only for early onset Alzheimer. These are the mutations: the amyloid precursor protein, the presenilin 1 [PS1] gene, and the presenilin 2 [PS2] gene. For the amyloid precursor protein gene and the PS1 gene mutations, those are exceedingly early onset, usually in the early 40s. The youngest patient I ever took care of who had a PS1 mutation was 30 when he got Alzheimer disease. His sister died at age 37, and his father died at 43 of Alzheimer. The PS2 mutation is a little broader range of age of onset, but I want to point out that this is only between 1% and 3% of Alzheimer patients overall. These are rare families.

And in these families, it’s no mystery. If you see a person who has early onset Alzheimer disease and has multiple family members who have the disease, then genetic testing definitely has a role, and they should be tested for the amyloid precursor protein, the PS1 and the PS2 mutations.

Jeffrey L. Cummings, MD, ScD: And those are available commercially, is that correct?

Elaine R. Peskind, MD: They are available commercially, CLIA [Clinical Laboratory Improvement Amendments] certified, the whole thing for genetic testing. And people in those families should have genetic counseling. There are more late-onset families in which there appears to be the same autosomal dominant pattern, the transmission. But we don’t yet have any genes or identified mutations that cause late-onset Alzheimer disease. This remains an active area of research.

There are also genetic risk factors for Alzheimer disease. It’s not having a mutational gene that definitely causes Alzheimer disease. There are different forms of genes that can confer increased risk. The absolutely most common disease is the apolipoprotein E [APOE] gene. It comes in 3 flavors, or alleles: the 2, the 3, and the 4 type. Of course, everybody has 2 genes: 1 from your mother, 1 from your father. And if you have 1 copy, but especially if you have 2 copies, of the E4 type, you have a much-increased risk of Alzheimer, at least to make the age of onset 10 to 15 years earlier.

But we don’t recommend people go out necessarily and have the APOE and genotype tested, because we don’t really have any way of altering the risk at this point. In fact, I did a 23andMe test, and I declined to know my APOE gene effect. I know there’s nothing I can do about it, so I’d rather not know. There are multiple other genes that have been shown to have small effects on increased risk, and it’s probably that this is a multigenetic-type of situation in which you might have to have a number of those to actually make an increased risk.

Jeffrey L. Cummings, MD, ScD: OK, and how do other people view the E4? That’s an area of controversy in that specialty.

Marwan Sabbagh, MD: Can I answer that, Jeff?

Jeffrey L. Cummings, MD, ScD: Marwan, we’ll start with you, but I’m sure everybody is going to have an opinion.

Marwan Sabbagh, MD: I don’t know if you saw, but on July 15, The Wall Street Journal had an article about APOE genotyping and whether it is a good idea or not. I’m 1 of the few physicians in the United States who orders APOE genotyping as part of my medical practice. I agree, we would never order it for people who were asymptomatic, and I did give my 23andMe APOE. But I order it as an added value to the clinical diagnosis. In MCI [mild cognitive impairment] and dementia, Alzheimer dementia, I tell them up front, I ask them if they want to know. Then I use it, and maybe I can explain a little on the why, because APOE-forced presence is a proxy measure of amyloid; if you’re positive, you’re more likely to have amyloid in your brain. So I use it, but I agree, we would not recommend people who are asymptomatic. If they’re normal, I will not recommend testing. For them I usually don’t do it.

But Elaine’s point is very important now that, in the last year, 23andMe will do it. People are actually getting tested for genetic risk every single day. Thousands of people a day are not realizing they’re getting their genetic risk for Alzheimer disclosed to them. And so I’m not sure that either societally or as a population we’ve actually dealt with the consequences of that information.

Jeffrey L. Cummings, MD, ScD: Richard, I think you had an opinion about this.

Richard Isaacson, MD: Sure. I was interviewed for that story, but my quotes were cut.

Jeffrey L. Cummings, MD, ScD: Here’s your forum now.

Richard Isaacson, MD: This is controversial, and this is tricky. I think from a brain-health risk-reduction standpoint, APOE testing has some utility in terms of predicting whether physical exercise or stopping smoking or addressing metabolic risk may be preferentially effective. Some of the dietary interventions—for example, low-carbohydrate diet, MCT [medium-chain triglyceride]—may be preferentially beneficial if the person is E4 negative.

This is in its infancy. I wish we could press the fast-forward button and catch up to cancer, and hopefully we’ll be using these results to inform care on a regular basis. I don’t think that time has come just yet.

That being said, I think there’s a lot of confusion. In men and African Americans, for example, the impact of E4 and their risk can maybe be different. Using E4 APOE genotype for diagnostic tests, I don’t recommend that. And understanding, as you mentioned, polygenic risk is really the key here. And you may have 1 E4, but the rest of your genetics are clean or you have some risk-reducing genes, your APOE E4 risk will be different from if you have multiple genes of the dozens that have been identified to amplify the risk.

Jeffrey L. Cummings, MD, ScD: Ali, do you have a preference?

Alireza Atri, MD, PhD: I agree. I think there’s much more research that has to be done on this, and it’s being done. I think the time will come where there will be these polygenic risk scores, and they’ll take some combination of your age and your APOE and other genes and family history, and that will be something that at different points in your life can actually tell you something and put you on different paths. But this personalized precision medicine isn’t there yet. It’s coming.

Right now, in the realm of actual diagnosis, there are no guidelines that actually advocate for this. There needs to be a clear understanding of what this means and disclosure. We’re not there yet for clinical practice. And I’ll say more about it toward the end when we’re talking about what we can do as far as practice guidelines, to tell how people think about it. Eventually it will come, but we’re not there yet.

Jeffrey L. Cummings, MD, ScD: My own view is that I’m working to empower the patient. If someone comes to me, even an asymptomatic person, and says, “Jeff, I want to know what my risk is,” I tell them what we can know, what E4 tells and does not tell, and if they want to pursue that after coming to understand what information is available from E4, I will do that. I’ll also do amyloid imaging if they are in the appropriate age group, because we know that people have amyloid in the brain for 15 years before they become symptomatic. If they want that information, and if they understand what the information means, I will seek it because I feel as if they are seeking the empowerment of knowledge, and I’m in a position to provide it, and I don’t feel like I’m in a position to deny it.

Elaine R. Peskind, MD: I don’t feel like I’m in a position to deny it, but I might counsel differently, and it can cause a lot of anxiety. It can, in some ways, interfere with the complete enjoyment of their healthy life that they have left. And that’s a concern to me.

Jeffrey L. Cummings, MD, ScD: Yes, and of course that should be part of the discussion that you have with them. I agree with that. This is sort of dangerous information, right? This is promethean, and you have to know how to manage it. But I do feel that our patients are more and more seeking information to make their own decisions, and that we have to be responsive to that.