Well, I think there are several reasons for this. There was, and still is, an active hunt for the genes underlying Alzheimer disease, and only one had been found at that time (APP), and that only in a very few rare early-onset cases. This was the first demonstration of the effect of an actual gene in the much more common late-onset disease. This was also one of the first successes in finding a gene in any complex disease, and has served as an encouraging example for other diseases. Finally, it was not just a simply finding of risk, but the dose effect of the APOE-4 allele that was so critical.

I was very active in the searches for the early-onset genes, and the collaborative group I was involved in was actively hunting down the PSEN1 gene (which we found two years later). It was obvious from that data that late-onset Alzheimer disease was a different entity and that PSEN1 would not be involved. This led naturally to working with the group with the largest set of late-onset pedigrees, and that was at Duke with Margaret Pericak-Vance. She had by then demonstrated genetic linkage to chromosome 19q13, so the only problem was to figure out which actual gene was involved.

As I already mentioned, this was one of the first success stories in finding genes in a complex disease, and gave great encouragement to other geneticists that such searches were not hopeless. Although there was some luck and serendipity involved, it is heartening to see that the same basic approach that we used—genetic linkage followed by association studies—has now been successful in several other diseases.

More specifically for Alzheimer disease, finding the APOE gene really helped refocus the molecular and physiological studies to understand how APOE fits into the overall pathophysiology, which we still do not really understand. The same is true for PSEN1, PSEN2, and APP. All have an effect at some level. We now have specific targets to help guide us in our understanding of the molecular processes.

Certainly there are innumerable ongoing studies to elucidate the role of APOE in the etiology of Alzheimer disease. Our collaboration with Dr. Pericak-Vance’s laboratory at Duke followed this effort by describing the protective effect of the APOE-2 allele, further demonstrating the importance of APOE in Alzheimer disease. We also determined that APOE represents only a portion of the genetic effect, and so we have been working to identify these other genes. We’ve identified locations on chromosomes 9 and 12 and are actively pursuing genes in these regions. We’ve also recently identified a gene on chromosome 10 that appears to influence age-at-onset in Alzheimer disease.

Ten years from now I expect we will have identified these genes and determined their potential interactions with each other. We will also have examined them for potential interactions with non-genetic influences, like NSAIDS use and smoking. This should lead to a much better understanding of the physiology of Alzheimer disease, and we expect, much better diagnosis and treatment.

Never give up! When we first published this result, it was roundly and loudly dismissed by researchers in Alzheimer disease and in genetics. It took several years to convince the body of Alzheimer researchers that this was a real effect, and that it represented a significant portion of the genetic effect in Alzheimer disease. Similarly, it took several years of amassing data before some geneticists agreed it was real. The role of chance events, chance conversations, cannot be dismissed either. You never know when the critical piece of missing information may appear in your lab or someone else’s lab. You just have to be prepared to accept what the data tells you, even if it seems unlikely.

Jonathan L. Haines, Ph.D.
Vanderbilt University School of Medicine
Department of Molecular Physiology & Biophysics
Nashville, TN, USA