Ronald C. Petersen, MD, PhD, discusses the relationship between genetics and the risk for developing Alzheimer disease, as well as highlights efforts of the Generation Program.
Ronald C. Petersen, MD, PhD: In the field of Alzheimer disease, broadly speaking, we generally talk about genetic characteristics. On the one hand, there’s a small proportion, maybe 1%, of all people with Alzheimer disease who have truly, dominantly inherited Alzheimer disease. In these families, people are at risk on a 50/50 basis. Half of the families will get it throughout the generations, and they tend to get it earlier in life.
Again, dominantly inherited Alzheimer disease really comprises maybe 1%, but this is very important because people who have the genetic mutation will get the disease 100% of the time. That affords us the opportunity to look at the biology of what’s going on in them. It turns out that here’s where abnormal amyloid processing is uniform in people with the disease. Therefore, that’s part of the amyloid hypothesis.
But what about the other 99% of the people with Alzheimer disease—so-called sporadic Alzheimer disease? Nevertheless, it still sort of runs in families, as most diseases do. If you have a first-degree relative with heart disease, cancer, or diabetes, your risk for those conditions is increased as well. The same thing is true with Alzheimer disease. If you have a first-degree relative with Alzheimer disease, you may have some genetic susceptibility.
There are probably 30 other susceptibility genes, meaning your risk is up or down depending on where you live with those genes. There’s 1 in particular called apolipoprotein E, which is a normal protein. We all have it. It serves to transport lipids around the body. It comes in 3 varieties: E2, E3, and E4.
It turns out that if you’ve inherited the E4 variety, from either mom or dad, your risk is up maybe 3- or 4-fold over the general population. If you’re unfortunate enough to inherit an E4 from mom and an E4 from dad, homozygous, then your risk is up maybe 10 to 14 times over the general population. Based on that, there actually is a clinical trial underway now called the Generation study looking at people who have 2 copies of the E4 apolipoprotein E gene. I think that the genetic characteristics are real. They may help us look at new pathways for treatments and are exciting avenues to follow.
Clinically, we generally do not do genotyping for people, with regard to their risk. This is because we would make the recommendation to individuals to do lifestyle modifications and get into clinical trials anyway. The genetic information may or may not be beneficial on an individual patient basis.