THE GENE HUNTERS.(Alzheimer's disease, Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

One morning last May in the Dominican Republic, two white S.U.V.s left the parking garage at the Gran Almirante Hotel and Casino, in Santiago, just as the gamblers and prostitutes were calling it a night, and headed half an hour north, to the town of Navarette. The lead vehicle was driven by Angel Piriz, a thirty-seven-year-old Cuban doctor who lives in New York. Beside him was Rosarina Estevez, a recent graduate of medical school in Santiago. Both were working as research physicians at Columbia University under the supervision of Richard Mayeux. For nearly twenty years, Mayeux, a neurologist, epidemiologist, and co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, has been compiling the world's most comprehensive genetic library of families with Alzheimer's, in an effort to uncover the biological origins of a disease that affects 4.5 million Americans. The family members are predominantly residents of the heavily Dominican neighborhood of Washington Heights, where the Taub Institute is based, or, like the family that the Columbia researchers were hoping to see, from the Dominican Republic itself.

Navarette isn't much of a town--a strip of concrete shops on either side of the road, and street venders selling pineapples and mangoes and fresh goat meat--and the family didn't have much of an address. "It's called Ginger Alley," Vincent Santana, the driver of the second vehicle, said, turning sharply into a narrow dirt track patrolled by chickens. Santana, who is in charge of the researchers' field work, gathered the notebooks and questionnaires they would need to administer the neuropsychological tests that, along with a medical exam, would determine who would be given a diagnosis of Alzheimer's disease.

Alzheimer's can be divided into two categories. One is known as early-onset Alzheimer's, which is rare, and tends to strike between the ages of thirty and sixty. Almost half of early-onset Alzheimer's is straightforwardly genetic, and follows the simple laws of Mendelian inheritance: if you are born with the mutated gene, you get the disease. Much more common is the late-onset disease, which tends to afflict people who are sixty-five and older. Because the prevalence of late-onset Alzheimer's increases as the population ages, the number of cases is expected to double in the next twenty-five years. Late-onset Alzheimer's is thought to be genetically influenced, too, but in a much less predictable way: it appears to involve perhaps half a dozen genes that, individually or in combination, increase one's risk of dementia. Researchers all over the world have spent the past decade hunting for these risk-factor genes, spurred by the impending public-health crisis and the daunting insufficiency of available treatments. They believe that working out the genetics of late-onset Alzheimer's, and thus finding molecular pathways that influence the course of the disease, was the best--and possibly the only--hope for finding a cure. So far, only one of those risk-factor genes has been conclusively identified. In May, though, as the Columbia researchers travelled through the Dominican Republic, drawing blood that was sent by FedEx each day to New York, it looked as if Mayeux's library might soon yield a second.

"This is a branch of the original family we saw here last year," explained Santana, a soft-spoken Dominican-American whose face was often knotted with worry. (Were the directions good? Would the subjects be home? Would they still be willing to volunteer? Would the data be useful? Would the blood spoil? And what about the Red Sox?) He directed Estevez to interview an elderly couple who lived across the way, then headed down the alley with Piriz, past houses made of concrete and tin, cutting through someone's kitchen and into a narrower alley and a warren of houses, asking for a man named Vargas. The proband--the first person in the family that Mayeux's team saw--died in February, at age ninety. "She's confirmed with the disease," Santana said. "In her generation, a couple of cousins and siblings have A.D. There's some first-cousin intermarriage. These people we're seeing today are her cousins. If we can find them."

As the researchers walked through the neighborhood, they attracted a parade of young boys, who eventually led them to Vargas's house, a spare, three-room dwelling. Vargas, a gaunt eighty-three-year-old who was tanned from a life growing bananas and tending rice fields, was lying, bare-chested and wearing blue shorts, on a bed with yellow smiley-face sheets. Surrounded by two of his five wives, four of his fourteen children, and an assortment of other relatives, he wasn't saying much. A few months earlier, he had been told he had pancreatic cancer and he wasn't expected to live out the year. Even so, he had consented to Santana's request to participate in the study.

Santana had known about Vargas for almost a year. In his notes from an interview with the proband in the spring of 2004, there was a reminder to identify and track down all her cousins and their siblings, in order to determine how they were related. Constructing accurate genealogies, which is what Santana does, is fundamental to figuring out how a disease travels among kin, which is what Richard Mayeux does.

"What day of the week is it?" Santana asked Vargas. A series of questions followed: "What is the date?" "What year?" "Where are we?" This was the warmup, and Vargas was doing O.K. He knew that he was in the bedroom, not the kitchen; he knew the year; he knew the season.