Genetic Insights

Nearly 40 years ago very little was known about Alzheimer’s disease, especially its causes. Early studies found a few families where Alzheimer’s disease was very common, suggesting that, in some cases, Alzheimer’s disease could run in families.  This suggested that genetics might play a role in Alzheimer’s disease. Through the hard work of many different researchers, by 1995 mutations (really rare variations in DNA) were found in three different genes (Amyloid Precure Protein, Presenilin 1 and Preselilin 2) that can cause Alzheimer’s disease. These mutations cause Alzheimer’s disease to occur early in life, thus often they are called “early onset” genes. However, the vast majority of Alzheimer’s disease, generally occurring after the age of 65 (“late onset”), remained unexplained. Dr. Pericak-Vance first recognized that many families with this “late onset” Alzheimer’s disease also seemed to cluster, or run, in families. 

By studying these families she was, along with her collaborator Dr. Haines, able to identify, in 1993, a different gene that had very common variations (usually called polymorphisms) that strongly changed the risk of developing Alzheimer’s disease. This gene, Apolipoprotein E, or APOE, has three common variations (also called “alleles”). Everyone has two copies of the APOE gene (one inherited from the mother and one from the father) and so have two alleles. The APOE-2 allele reduces someone’s risk of Alzheimer’s. Unfortunately, it is also the least common allele. The next most common allele, APOE-4, raises the risk of getting Alzheimer’s disease significantly. The most common allele (APOE-3) doesn’t affect the risk of developing Alzheimer’s disease. APOE is the most important, and strongest, biological risk factor for Alzheimer’s disease. Since these early studies clearly showed that genetics was very important in understanding the risk of Alzheimer’s disease, researchers from around the world have used rapidly improving genetic techniques to find additional genes that help us understand what happens in Alzheimer’s disease. Genetics has told us that cardiovascular disease and in immune processes are also important in Alzheimer’s disease. We also now know that the genetic risk of Alzheimer’s disease changes depending on ancestry. Although the genes themselves are the same, we are just now learning that individuals who have African ancestry have a different genetic risk profile. For example, the risk of Alzheimer’s disease if you have an APOE-4 allele is less if you have an APOE-4 allele derived from Africa, but we don’t yet know why. Similarly, individuals of Hispanic ethnicity have different risks depending on their specific ancestry.

So the big question is why is genetics so important? We know that the success of developing new drugs is much better is we understand the genes involved in in Alzheimer’s disease. And we need to know how genetics varies across ancestries if we are going to find effective treatments for Alzheimer’s disease that re helpful to everyone. There is so much still to be learned so we can accelerate the development the best possible treatments for this devastating disease that is helpful to everyone.