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Sometime later, two more early-onset Alzheimer's genes were found, Presenilin-1 and Presenilin-2. Like APP, these genes were dominant; a child who received just one gene from either parent would inevitably get the disease. One of the most tragic examples involved a 4,000-member Colombian family that had been haunted for generations by Alzheimer's. Yet such cases, researchers were only too well aware, accounted for merely a small fraction of all cases of Alzheimer's disease. Still other genes, they reasoned, must be involved in the great majority of cases--those in which dementia does not strike until one's seventh, eighth or ninth decade of life.
In 1992 Dr. Allen Roses, a rapier-tongued contrarian then at Duke University, challenged the beta-amyloid orthodoxy. He announced that he and his colleagues had found a major Alzheimer's-susceptibility gene that affected the late-onset forms of the disease. It was the gene for APOE4, a common variant of the APOE lipoprotein, which is one of the many workhorses of the body's cholesterol-transport system. What, everyone wondered, could this lipoprotein, a known risk factor for heart disease, possibly have to do with Alzheimer's? Very quickly, many concluded that Roses could not be right.
What followed was a sustained scientific Donnybrook. Roses, whose penchant for plain speaking had long irritated his peers, was attacked--viciously, he says--and he proceeded to fight back in kind. He dubbed his opposition the Amyloid People and mercilessly taunted them. The plaques, he argued--and still argues--were just tombstones, markers of places where brain cells had died, not the cause of death. On one occasion, Roses sent Selkoe, who had co-founded a company to work on Alzheimer's therapeutics, a photograph inscribed with the message "Dennis, you're wrong--but you're going to be rich."
In the end, Roses won the APOE4 argument. Everyone now agrees that this gene is indeed a major risk factor for Alzheimer's disease. But unlike APP and the Presenilins, it is a susceptibility gene. People who carry it do not invariably develop Alzheimer's, but if they do, their brains appear to be more riddled with plaques and tangles than the brains of Alzheimer's patients who carry slightly different versions of the APOE gene. Even more intriguing, APOE4 appears to have a broad impact on the well-being of nerve cells. Among other things, people who carry two copies of APOE4 have more difficulty recovering from strokes and traumatic head injuries; they are also more likely to sustain brain damage during cardiovascular surgery.
In all, APOE4 may contribute to the development of more than 60% of all late-onset Alzheimer's cases. But that leaves the other 40% unaccounted for. And at this moment, many scientists, including Roses, are racing to identify still other Alzheimer's-susceptibility genes. Rudolph Tanzi, a geneticist from Harvard, believes that he has nabbed a prime suspect on chromosome 12, a gene called A2M. But he has yet to convince his critics. Two years ago, when Tanzi presented his data at an Alzheimer's meeting in Amsterdam, his evidence was brutally attacked. "I wish I'd been wearing chain mail," he jokes. "I felt as if I'd been shot through with spears and arrows."