By David N. Leff
You don't have to be gerontic to contract Alzheimer's disease (AD), but it helps. Some 95 percent of AD patients are diagnosed after 60 years of age. These cases are known as late-onset AD - LOAD.
Early onset AD (EOAD), diagnosed in the prime of life, under 60 - sometimes decades before LOAD - represents more than a mere statistical aberration. People who got the disease younger, rather than older in life, provided the first genetic evidence of what perpetrates AD altogether.
"The three genes associated with early onset AD," recalled neurogeneticist Rudolph Tanzi, who directs the Genetics and Aging Unit at Harvard-affiliated Massachusetts General Hospital, in Charlestown, "are those expressing APP, amyloid precursor protein, and the two presenilins.
"It was back in 1992," he recalled, "that a number of research groups published three different papers stating specifically that in EOAD it looked as if there was a major gene on chromosome 14 - and the worldwide race began. It took three years before [geneticists] in Toronto found that second EOAD gene - APP was the first - which ended up being presenilin-1. Soon after, we found presenilin-2 on chromosome 1.
"A similar race," Tanzi continued, "now begins for LOAD. The gene for APOE, apolipoprotein E, sits on chromosome 19. We know there's a major LOAD gene on chromosome 10, so we and at least two other groups are racing to locate the chromosome 10 gene and its AD-inflicting mutations."
The three collegial, competitive teams coordinated their research papers to appear as a set in the issue of Science dated Dec. 22, 2000. Tanzi is senior author of the article titled, "Evidence for genetic linkage of Alzheimer's disease to [the long arm of] chromosome 10."
At Washington University School of Medicine in St. Louis, neurogeneticist Alison Goate authored a companion article bearing the title, "Susceptibility locus for Alzheimer's disease on chromosome 10." And the third paper, by pharmacologist Steven Younkin at the Mayo Clinic in Jacksonville, Fla., carries a more amyloidal spin in its title: "Linkage of plasma Ab42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees."
The Enemy - Beta Amyloid
Tanzi explained, "All of the genes we found so far in AD have in common that they lead to an increased accumulation of beta amyloid in the brains. [Senile neuritic plaques, the hallmark of AD, consist mainly of beta amyloid.] It looks," he went on, "as if chromosome 10 will follow suit. Two of the three papers, ours and Goate's at Washington University, show genetic linkage to AD. The third paper, from Mayo Clinic, with Younkin, shows linkage to increased accumulation in the blood of the amyloid-beta peptide. They analyzed AD families, some of which have increased beta peptide in their blood plasma. And they found linkage to chromosome 10 in the same region - not to the disease but to that particular trait. So just like APOE and the two presenilins," he added, "I'd include alpha-2 macroglobulin as well. We also see an association of alpha-2M carriers."
On this score, Tanzi observed, "We were among the first in AD research to look at genes using family-based association as well as traditional controlled linkage analysis. That's how, back in '98, we had identified an association with alpha-2-macroglobulin. That gene, on chromosome 12, remains controversial because family-based association sees alpha-2M more readily than controlled studies do.
"That alpha-2M marker was involved in breaking down amyloid. And so are a number of enzymes, including IDE, the insulin-degrading enzyme.
"There are four established Alzheimer genes. Three early onset ones are APP, and presenilins 1 and 2. Plus one LOAD - APOE. We would argue," Tanzi said, "that the fifth AD gene - and the second LOAD one - A2M on chromosome 12, is controversial. The chromosome 10 gene, we would argue, would be the third LOAD gene, or the second if we don't believe A2M. In any event, I would guess from the initial data that the chromosome 10 gene could very well be more important than both A2M and APOE. We still have no definite answers as to what the gene is. Or whether IDE is it. So we're testing candidate genes, including IDE, for variants that show association. Our ultimate goal is to find the pathogenic mutations themselves.
"Many of us in AD genetics," Tanzi went on, "believe there are probably four or five major genes yet to be discovered in the LOAD form beyond APOE. Chromosome 10 is clearly one of them, and I wouldn't be surprised if the gene there, once we find it, is a more major AD gene than APOE. The early results are so strong. But meanwhile we and other groups have been following up leads on other chromosomes. From the biology standpoint, we were entertaining candidate genes, and one of our interests has been proteases that break down amyloid. That's how we got to IDE on chromosome 10."
One Risk Factor Is Not Enough
Tanzi made the point, "You cannot predict AD with APOE alone. It can only be used in a differential diagnostic. That means, you can't be sure it's Alzheimer's - because to be sure you need to look in the brains post-mortem. EPOE has been suggested, if somebody already has dementia, as a way of further testing to get a better idea if it's AD or some other form of cognitive failure.
"Once we have three or more reliable risk factors," Tanzi observed - "and we only have EPOE so far - we can start thinking about doing genetic testing for AD prediction or diagnosis. At that point, all kinds of caveats come to mind. The three main ones are: First, how reliable is the test? Second, is that information privacy protected? I think we still have a long way to go in this country to ensure genetic privacy and protection against discrimination due to one's genome.
"Now let's say we have a reliable, protected test. Then the third question becomes: What good is it? As there's no drug therapy yet, there's nothing we can do about it. The drugs being developed are hitting beta amyloid, either trying to stop its production or clear it away - preferably both. All of that has been supported by genetics, with the genes found so far," Tanzi concluded, "I'm very optimistic about the future."