^{This originally dates back to early 1987 when there were four different papers published describing the fact that amyloid plaques are made up of amyloid beta protein derived from the amyloid precursor protein (APP). The first mutation in the amyloid precursor protein was found in 1991 by Blas Frangione’s group. He found a mutation in APP that caused vascular dementia, a vascular form of Alzheimer’s disease. Then John Hardy’s group in England found another mutation in APP, responsible for a classic form of early-onset Alzheimer’s. As it turns out, mutations in APP are pretty rare. There are probably about 15 and they account for a 1% slice of Alzheimer’s disease—a small, small, small slice. About 5% of Alzheimer’s disease strikes patients under 60 years of age. The majority of those are familial, autosomal dominant forms of Alzheimer’s. And APP is responsible for probably five or ten percent of that 5%.}

^{Now fast-forward to around 1992. We knew that the bulk of early-onset familial Alzheimer’s is not due to APP mutations. There had to be other genes and finding those genes would shed a lot of light on the biology. A number of groups, including a group collaborative with ours—my group was not the major driver—found a linkage of Alzheimer’s disease to chromosome 14. Between 1992 and 1995 there was a three-year race to clone what looked like it would be a major early-onset gene on chromosome 14. That ultimately led to the highly-cited Sherrington paper in 1995. That represented a collaboration between Peter Hyslop’s lab—he is the last author—where Sherrington was a post-doc, and our group, and a number of other groups, as well.}

^{This gene encoded a protein the likes of which we’d never seen before. It had a few homologies here and there with other genes in C. elegans, but for the most part we could only guess about its function. It was a protein with multiple transmembrane domains. It was serpentine; it snaked in and out of the membrane eight times. We named it presenilin-1, because of pre-senile dementia. Now we know of about 140 autosomal-dominant, fully-penetrant mutations in presenilin that cause this early-onset form of Alzheimer’s, usually familial. As it turns out, about 1% of all Alzheimer’s cases occur before age 50, and in that 1%, the vast majority are due to presenilin mutations. If you have a case come in under 50 years of age, the first thing you do is look at presenilin.}

^{After presenilin-1, we pulled out a cDNA for what turned out to be homologue for presenilin-1, called presenilin-2, which mapped to chromosome 1. I knew Gerry Schellenberg; he is the second-to-last author on the Levy-Lahad paper. I knew he had a paper submitted and that he might have also talked about a linkage he had for another familial Alzheimer’s disease locus on chromosome 1, and so I called him up and told him that we just found a homologue of presenilin-1 on chromosome 1 and it might be his gene. So we looked to see if this gene mapped specifically in the little tiny region of chromosome 1 where he knew his gene should be and sure enough it did. And around the same time both of our labs came across an amino acid mutation that showed that presenilin-2 was an Alzheimer’s gene. So we published that with two first authors, one from his group, Levy-Lahad, and one from ours, Wasco.}

  ^{So this was an effort to make sure credit was properly shared by the two labs?}

^{I’ll tell you a funny story about that. We both got the mutation around the same time, but the way things were we wanted to make sure one group wasn’t piggy-backing off the other—in other words, one lab just saying "we see it, too." We arranged it so that when he told me he had the mutation, and I told him we had the same thing, that same day I had to FedEx him the autoradiograph of the sequencing gel. That way he could be sure we had it, too.}

  ^{Where do these Alzheimer’s genes leave you in terms of understanding the genetic basis and underlying biology of the disease?}

^{As of 1995 we had identified three different genes that can cause early-onset familial Alzheimer’s disease. And yet these three mutations still only account for about half of early-onset disease. So we still have to find the genes responsible for the other half.}

^{Of those three genes we know of, there are probably about 140 mutations of presenilin-1, eight in presinilin-2, and 15 or 16 in APP. That list is growing; what we have learned since then is that all these mutations, with very few exceptions, do the same thing. They increase in the brain the ratio of amyloid beta 42 to amyloid beta 40.}

  ^{What’s the significance of that ratio?}

^{If you look at amyloid beta in the brain, about 90 percent is amyloid beta 40, and the remaining 10 percent has two extra amino acids on the C terminus, making it amyloid beta 42. Amyloid beta 42 is the main culprit of the disease. It forms amyloid much more readily. It’s harder for the brain to clear away. It’s more toxic. What we learned is that even small increases in how much amyloid beta 42 you make, relative to amyloid beta 40, causes problems. It’s not the absolute increase in 42; it’s the ratio. If this is increased even slightly, just 10, 20, or 30 percent, compared to amyloid beta 40, it is enough to cause early-onset Alzheimer’s disease. Some of the presenilin-1 mutations, for instance, can cause Alzheimer’s disease as early as the late teens or early 20’s, and in those we see a pretty robust effect on the 42 to 40 ratio going up.}

  ^{What are the clinical implications?}

^{This has been a great clue for drug development. A lot of drugs are designed to just go in and hit amyloid beta. My opinion is if you want a laser strike with the least side effects, you go in and hit amyloid beta 42. And I have started a company in San Diego to do just that, to find drugs to reverse what the genetics tell us is happening. The genetics say that the ratio of 42 to 40 is critical. I argue the safest and most specific drug is the one that goes in and hits 42 and tries to decrease that ratio.}

  ^{What is the biggest challenge in doing this research?}

^{Before I get into that let me tell you about one other thing we’re doing here. We have a huge genetics and genomics program, which is funded by the National Institute of Mental Health and the National Institute of Aging, devoted to finding all the other Alzheimer’s disease genes. We’re making great progress. We’ve just published a genome screen showing the locations of the remaining genes, and we have candidate genes on several different chromosomes. This is all a work in progress. And some of this has been submitted for publication. So if you go from major genes to minor genes and modifiers, we’re probably looking at least a couple of dozen genes involved. I’m hoping that within five to ten years—and I think this is being pretty realistic—we will have enough genetic data to reliably predict who is at the greatest risk for the disease. But if you can predict the disease, you have to empower those individuals with a prophylactic strategy. That’s where the drugs come in. So genetics on the one hand allows us to make progress predicting the disease, and on the other hand allows us to discover drugs best suited for those at risk for a given genetic factor. The mantra we have here is that the goal is early prediction, early prevention.}

^{When I give talks to wider audiences, I usually say that 50 years from now, with the advent of progress of genomic medicine, we will look back at the times when we waited for diseases like Alzheimer’s, diabetes, and cancer to strike first before we treated them and we will see that as barbaric. We will no longer have to wait for diseases to strike. For the big four age-related diseases—Alzheimer’s, diabetes, heart disease, and cancer—we will predict early and prevent, and we will customize treatment to match the genetic profile.}

^{That said, the biggest challenge, far and away, is funding. I don’t mean to be shallow, but the number one challenge is having to spend so much time and effort just to obtain the funding to do the things we know we need to do. There’s so much we know we have to do, and we know how many people it will take, and we know how much time it will take to get it done, and the limiting factor on that progress is funding. And the greatest distraction to spending time getting that science done, is having to constantly spend time writing grants and progress reports. When you should be using your brain for creative ideas, you’re using it to obtain funding. That’s the biggest challenge.}

  ^{Well, once you’re in the laboratory, what do you see as the biggest challenge to the research itself?}