A recent study published in Nature Medicine offers evidence that genetics may be a direct cause of a specific form of Alzheimers disease and not merely a risk factor. While most patients currently do not have a clearly identified cause of this devastating illness, researchers found that people with two copies of the gene variant APOE4 are at extremely high risk of developing Alzheimers. The finding led them to recommend a new designation that takes this into account, which could lead to up to a fifth of Alzheimers patients being classified as having a genetically caused form of the disease. The shift eventually could lead to earlier diagnosis and treatment and affect the search for therapies. Reisa Sperling, a neurologist at Mass General Brigham and an author of the study, explains the importance of the findings. This interview has been edited for clarity and length.

Your study highlights a new, clearly identified genetic component to Alzheimers disease worthy of a new designation. Could you explain why thats significant?

Designating this form of Alzheimers disease means a group of people who are extremely likely I wont say absolutely, but extremely likely to develop Alzheimers could be treated earlier. This could really have an impact on preventing dementia.

The second thing is theres been an ongoing debate about whether Alzheimers disease has anything to do with amyloid plaques or not. And in this group, they begin to have buildup of amyloid plaques and tau tangles in their late 50s and early 60s, and the likelihood that they will develop symptoms of Alzheimers disease is extremely high. So it creates another link in our understanding of the disease process.

And finally, this is a bridge between the rare forms of genetically determined Alzheimers disease that are 100 percent penetrant and often affect people in their 40s and 50s. Those cases are often considered such a rarity that theyre not representative of Alzheimers disease. So people with two copies of APOE4 are a bit in the middle. This new study really suggests that their biomarkers are similar to what we see in these rare autosomal dominant diseases, and over 90 percent will develop Alzheimers pathology in their brains. It links the rare genetic forms of Alzheimers to what we call sporadic late-onset Alzheimers disease.

Part of this new classification would also make this type of Alzheimers one of the most common genetic disorders in the world. Are there benefits to having it classified that way?

I dont know that Im the best person to opine on that, but I certainly think there may be important reasons. For example, eventually getting insurance coverage for individuals who are below the age of 65 and need rapid evaluation and treatment for Alzheimers disease. Alzheimers disease often doesnt get diagnosed in these individuals because people think theyre too young. Additionally, they may not have insurance coverage for all of the medications required for treatment.

I do think it is important that this is recognized as one of the more common genetic links to Alzheimers disease and leads the way to one day being able to treat people who have a strong family history and genetic predisposition. Then we can really think about being aggressive and treating patients early.

Somehow, we have to turn these findings to instead of being scary for people being a sense of hope.

Weve known for a long time that there is a genetic component to Alzheimers disease. Is this one of the first studies to show such a specific genetic link?

No. As I mentioned there are these rare genes that weve known for more than 20 years that are very specific and cause Alzheimers disease at a much younger age. But this data really suggests that people who have two copies of this particular allele, APOE4, have such a high likelihood of developing Alzheimers disease.

So its not the first genetic link, but it is the first large study that convincingly says having two copies of this gene really increases the likelihood you will have Alzheimers disease. And its a more common gene; these other known genes are very rare. But with APOE4, its estimated that up to 15 percent of Alzheimers patients carry two copies of these alleles (although I will say that estimate is a little different across studies). It is much more common than these very rare autosomal dominant forms.

How common is it in the general population to have two copies of that gene?

Estimated, about 2 percent of the population, so its not that common. People having at least one copy of APOE4 is fairly common. Depending on which part of the world youre from, that can be up to 25 percent. But having two copies is still pretty rare.

There is still so much that we dont know about Alzheimers, but it does seem to be fueled by both genetic and environmental factors. In what ways does this research help push our understanding of the disease overall?

Thats a great question. And for me, this research really does provide support to both camps. One, the likelihood that people with these genes will develop amyloid plaque by the time theyre age 65 is somewhere between 75 and 95 percent. To me that suggests that it is genetically driven.

But there is a variability in the range of when people develop symptoms. And that suggests that there might be environmental or lifestyle factors that can make peoples brains more resilient, or conversely, more vulnerable. This research really supports both ideas that genetics is a major driver in Alzheimers disease, but you can modulate your risk of showing symptoms.

Would it be beneficial for people to know early on if they are carriers of these genes?

At this moment, I do not recommend that people who dont have symptoms get genetic testing or blood-based biomarker testing. I hope that recommendation will change greatly over the next few years.

There are large-scale clinical trials, including the one I run. Were recruiting people who have evidence of amyloid buildup, but dont yet have symptoms, and were recruiting a lot of people with a family history and have copies of APOE4. If that study and other studies like it succeed in treating people before they have symptoms, then I would recommend testing and trying to get treatment as soon as possible.

But we dont have that available right now, and I just think we dont yet know what to do with that information before people have symptoms.

If this new classification did occur, what areas of further research would you be most excited to pursue?

Number one for me is we need to be able to offer treatments to those patients. Right now, theres actually a black-box warning on some currently approved Alzheimers treatments that cautions treating people who have two copies of APOE4 because the risk of side effects is so great. I want to redouble my efforts to make sure we can offer disease-modifying medications in a safe way.

Number two is about the environment. Im quite interested in what it is that modulates whether people get symptoms sooner rather than later, with this buildup of amyloid thats genetically determined. How do we understand what factors were protective? Thats a very important area of research to help us understand what can modulate peoples risk of symptoms in the setting of a very strong genetic predisposition.

We talk about this in the study, but I think its also important to mention that these studies mostly observed white majority populations. And one of the things we desperately need to know is whether these findings are also true in more ethnic and racially diverse populations. There is some evidence that APOE4 might have a slightly different effect on amyloid in populations who come from communities of color.

Similarly, there are slight differences in the sex effects: Women APOE4 carriers have more likelihood of developing symptoms. I think its really important to get more information on representative populations, especially from communities of color, and really help us develop treatments that will work best for everybody.

For people who have Alzheimers or loved ones with Alzheimers, how do these findings offer hope or shed light on the disease?

This is another tool to be able to find people who have Alzheimers disease at an earlier stage and treat them earlier. My dad and my grandfather died of this disease, and Im a clinical neurologist. When I see people with symptoms, I think this is helping us learn about the underlying causes and will help us in accelerating to find good treatments.

I think it will both help the next generation of people who are likely to develop Alzheimers disease, but it will also help us treat people who already have Alzheimers disease symptoms because every little bit of information helps us develop better treatments for all.

I really hope this research doesnt have the effect of just scaring people. I hope it will instead say, These are important clues so that we can treat people earlier and hopefully prevent dementia.

Somehow, we have to turn these findings to instead of being scary for people being a sense of hope. I hope this means we will be able to find people and treat them before they develop symptoms.

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Link:
Alzheimer's study suggests genetic cause of specific form of disease Harvard Gazette - Harvard Gazette