Sue Halpern
802-388-3673
One morning last May, two white SUVs left the shade of the parking garage at the Grand Almirante Hotel and Casino in Santiago, Dominican Republic as the gamblers and prostitutes were calling it a night, and headed north to rural Navarette. The lead vehicle was driven by Angel Piriz, a thirty-six-year-old Cuban doctor who now lives in New York. Beside him was Roserina Estevez, a recent graduate of medical school in Santiago who, like Piriz, is working as research physician at Columbia University under the supervision of Dr. Richard Mayeux. For nearly twenty years Mayeux, a neurologist, epidemiologist, and director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, has been compiling what has become the most comprehensive genetic library of families with Alzheimer’s disease in the world. The family members are either residents of the largely Dominican neighborhood of Washington Heights where Columbia Presbyterian Hospital is located or, like the family 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 vendors selling pineapples and mangoes and goat meat so fresh that the goats are still tethered to the stall—and the family didn’t have much of an address. “It’s called Ginger Alley,” said Vinny Santana, the driver of the second vehicle, turning sharply into a narrow dirt track patrolled by chickens. Piriz, who had briefly gotten lost, pulled in behind Santana, and without much conversation, the two doctors assembled their medical kits. Meanwhile, Santana, who is in charge of the field work, gathered the notebooks and questionnaires they would need to administer the neuropsychological tests that, along with the medical exam, were crucial for determining who would be diagnosed with Alzheimer’s disease, and who would be said, so far, to be exempt.
Alzheimer’s, which ultimately may turn out to be too broad a term to be of much use clinically, is typically divided into two types. There is the early-onset variety, which tends to strike between the ages of thirty and fifty and is very rare, occurring in less than five percent of cases, and there is the much more common late onset disease, which tends to afflict people who are sixty-five and older. Early onset Alzheimer’s is a genetic disease that follows the simple, deterministic, law of Mendelian inheritance: if you are born with the gene, you get the disease. Late onset Alzheimer’s is thought to be genetic, too, but in a much more messy way: rather than being caused by a single gene, it appears to be the result of a passel of genes that, individually or together, are believed to increase one’s risk of dementia. So far only one of those risk factor genes has been conclusively identified and confirmed. In May, though, as the Columbia researchers trolled the island, drawing blood that was sent by courier each morning to New York, it looked like Mayeux’s library, which contains DNA and neuropsychological data collected from over 13,466 participants, most of whom either have Alzheimer’s or are related to someone with the disease, 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 they get enough of it? Would the blood spoil? Would it make it through customs? And what about the Yankees?) 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 dim, fly-infested kitchen to a narrower alley and a warren of corrugated houses, asking for a man named Matias de Jesus Vargas. “The proban—which means the first person in the family we saw—who was in her late 60s--died in February,” Santana said. “She’s confirmed with the disease. In her generation a couple of cousins and siblings have AD. One of her children has it, and a couple are borderline. There’s some first cousin intermarriage. These people we’re seeing today are her cousins. If we can find them.”
As they went they attracted little boy after little boy, a whole parade of them, who eventually led the researchers to a spare, three-room dwelling: Matias’ house. Matias, a gaunt eighty-three year old man, tanned from a life growing bananas and tending fields of rice, was in bed lying bare-chested in blue shorts on top of yellow smiley face sheets, surrounded by two of his five wives, four of his fourteen children, two of his daughters’ daughters, a great-granddaughter, a brother, two cousins, the sister of one of his wives, and an indeterminate number of children who might have been related to the assortment of adults. He wasn’t saying much. A few months before he had been diagnosed with pancreatic cancer and wasn’t expected to outlive the year. Even so, he had consented to Santana’s request to participate in the study.
Although Vinny Santana was meeting the man in the bed for the first time, he had known about Vargas for about a year. In his notes from his interview with the proban in the spring of 2004 there was a reminder to identify and track down all her cousins and their siblings, in order to map out how they were related. Constructing accurate genealogies—what Vinny Santana does--is fundamental to figuring out how a disease travels among kin—what Richard Mayeux does.
“I started off thinking Alzheimer’s was not a genetic disease,” Mayeux told me the first time I visited him in his remarkably neat office on the 19th floor of Columbia Presbyterian Hospital last November. (The office of a man who is rarely at his desk.) “I thought it was environmental, associated with aging. But the accumulating data convinced me, seeing that this disease tracks in families. It doesn’t always follow a pattern, but it does track in families, so that if you have family members with the disease you have a much higher risk of getting it, and siblings with the disease give you an even higher risk. The evidence was very hard to counter.”
Mayeux selected a bound volume the size of Webster’s Third from a set of nearly identical bound volumes that took up most of a wall, and began flipping through the pages as he spoke. It was an encyclopedia of the family trees of people in his study that showed who was related to whom and which ones had the disease, who was disease-free, and who was living in the border town between lucidity and dementia.
“What we wanted to do was find a population where we thought the rates were higher, because the thing about genetics is that if you try to identify people who carry the gene, you are looking for unusual people. It’s not like epidemiology, where you try to get random samples of random people. Genetics is just the opposite. You want a biased population. You want families where there is more of the disease because you have a better chance of figuring out what the gene is.
“That’s how we stumbled into this study of people in the Dominican Republic. We noticed when we were doing a general population study of elderly people who live around the hospital, that Dominicans had about three times the rate of Alzheimer’s disease compared to the whites and blacks in the community. So you have to ask yourself why that would be. Then it starts to explain itself that at least in the DR, Dominicans tend to marry other Dominicans, and you don’t have different populations moving in there. You have a smaller genetic pool, and first cousins marrying first cousins, so the gene pool tends to stay enriched. Here’s one,” Mayeux said, pointing to a page in the book. “These two people are twins. Look at how many people who are related to them are affected and how many are beginning to experience symptoms.”
Mayeux, who was raised in Louisiana, talks with a lingering nasal drawl that makes it seem like he’s got all the time in the world, a pleasantly deceptive cadence that belies an edge of impatience, a chronic busyness. He is constantly in motion, typically late, a consummate plate-spinner. He is driven, but so ready to credit colleagues and collaborators that his own ambition can sometimes seem evanescent. A football player at Oklahoma State in the nineteen sixties, and a weekend soccer coach now, Mayeux has brought the ethos of the playing field into the search for Alzheimer genes: it’s all about teamwork. At 59, he says he is too old to be motivated by dreams of personal glory.
Mayeux is tall, fit, with a full head of brown hair going slowly to gray and a mostly unlined brow. His colleagues joke that he’s a graduate of the Dick Clark School of Aging, though in the looks department he favors the actor George Clooney. (“Can you believe he’s so smart and so handsome?” the middle-aged daughter of one of Mayeux’s patients whispered to me one day in the waiting room of Columbia’s Memory Disorders Clinic, as Mayeux breezed by. “And so nice, too,” added her mother, who is not demented.)
Unlike Clooney, though, Mayeux hasn’t spent much time in the ER. Almost from the start of his training, first at the University of Oklahoma, where he went to medical school, and then at Boston City hospital where he did his internship, and at Columbia, where he was a resident, Mayeux has studied diseases of the brain: epilepsy, Parkinson’s, Huntington’s, Alzheimer’s. Though he continues to do research and to see patients, Mayeux is also an adroit administrator, overseeing a staff of 138 neuroscientists, geneticists, psychologists, epidemiologists, neurologists, data entry clerks, cell biologists, biochemists, genetic counselors, and animal modelers spread over two floors of the hospital, as well as in outposts at the medical school and Columbia’s Neurological Institute. Many, like Dr. Joe Lee, who sifts through the 30,000 genes that comprise the human genome looking for a genetic quirk that could explain the colonization of the brain by sticky plaques and neurofibrillary tangles—the signature pathology of Alzheimer’s disease--and Dr. Scott Small, a neurologist who has developed a method of using magnetic resonance imaging to look deep into the brain and see trouble before trouble has a name, took the conventional academic route of medical degrees and doctorates. But a surprising number never intended to chase what Mayeux calls “the great white whale of neuroscience.” There is a former Wall Street accountant who deconstructs MRI data and a German astrophysicist who develops diagnostic algorithms. There is Angel Piriz, the Cuban doctor, who spent three years working for a Manhattan construction company until he found the Columbia job on the internet. And there is Vinny Santana, who was a twenty-year-old a security guard in the Presbyterian Hospital emergency room when he was offered extra hours to escort Mayeux’s field researchers to interviews in Washington Heights, his home neighborhood. Eventually Santana became one of those researchers himself, expert in administering and scoring complex neuropsychological tests, and then the research coordinator, and now, at thirty-five, a co-author on four of Mayeux’s scientific papers.
The neuropsychological tests that Santana and the other field researchers were carrying to Ginger Alley were developed by Yaakov Stern, a psychologist who has worked with Richard Mayeux for 21 years. The battery assesses a variety of cognitive functions, many having to do with memory, since in Alzheimer’s disease, memory—for the names of things, for words, for recent events—tends to deteriorate profoundly early-on. Indeed, researchers at NYU and the University of California, Irvine, have found certain of these tests to be predictive of disease. And in Yaakov Stern’s lab it had been observed that results on a verbal fluency exam appeared to foretell who, among the afflicted, would die the fastest.
“My feeling is that the best tool we have for diagnosing AD is neuropsych,” Stern, a rangy man with a loping gait, said last winter as we walked back to the hospital from the Neurological Institute, where he had just given grand rounds on the concept of “cognitive reserve,” the reservoir of synapses and neurons that lets some people, even those with plaques and tangles, resist dementia. “Neuropsych is sensitive to early changes. But the point of transition where someone starts to develop problems, well, it’s hard to make a fast rule about any one person that they are definitely going to develop Alzheimer’s disease.”
To determine who, in the Dominican population, had the disease—as opposed to who will develop the disease—Stern and his colleagues have come up with a mathematical formula that gives them a score that they have found to be clinically reliable.
“When someone comes to our Memory Disorders Clinic in New York, we try to use the best norms for them based on their education, their age, even their gender,” Stern explained. “That’s the typical neuropsychological approach. It asks: what can we expect from this person. And if they deviate from the norm then we can assume there is some deficit.
“In the genetics study in the Dominican Republic, we decided to use an algorithm because, first of all, we didn’t know what the norms there were when we started, and secondly we wanted to be consistent and unbiased. So for every test we have a cut score, below which we’d say that’s bad, and if a person meets our criteria for cognitive deficiency they have cognitive deficiency, and if they don’t, they don’t—for the purposes of diagnosing dementia. The idea behind the algorithm is that we wanted memory to be the gatekeeper. If someone didn’t have a bad memory, I didn’t want to say they had dementia. Most of the time the algorithm works pretty well.”
“What day of the week is it?” Santana was asking Matias de Jesus Vargas. “What is the date? What year? Where are we? Can you count backward from twenty? Can you name the months of the year in reverse order? I am going to tell you a name and address and I want you to repeat what I’ve said: Juan Perez, Avenida Duarte cuatro y dos, Samana.” This was the warm-up, and Vargas was doing okay. He knew he was in the bedroom, not the kitchen; he knew the year; he knew it was summer, though technically it was spring.
Santana leaned in close. “I’m going to read you a list of twelve words, and when I’m done I want you to repeat them back to me. Juevo,” he began. “Lava.” Vargas fingered the religious medal he wore around his neck and looked lost. “I can’t remember,” he said, pointing to his head. In the algorithm developed by Yaakov Stern, the cut score on this test is 25: if someone, given the opportunity to repeat any of these twelve words six times, for a top score of seventy-two, can’t get to twenty-five, he can be considered for “case status.” When the test was over, Vargas’ score was fifteen.
In the next room, Angel Piriz was going through the same routine with one of Vargas’ wives, a short, seventy-year-old woman in a faded housedress and heel-worn flip-flops, who was eyeing him warily. “Do you ever find yourself getting lost?” Piriz asked. “Hell no,” she said. He took her blood pressure, looked into her eyes, tested her reflexes. Then he put on green latex gloves, took out a syringe, and prepared to draw her blood.
Across the street from Columbia Presbyterian Hospital, at the Russ Berry Biomedical Center, there is a room with a bank of industrial freezers containing 28,544 vials of blood. In 1986, when Mayeux inaugurated what is known as the WHICAP study, a sweeping epidemiological investigation of the health and habits of 2500 elderly residents of Washington Heights, he instructed the researchers to collect blood in addition to recording demographic and medical data. The field of Alzheimer’s genetics was in its infancy and putting blood on ice was either capricious or prescient, depending on who was paying the bill. It had only been three years since scientists at the University of California, San Diego, succeeded in isolating amyloid, the key constituent of the plaques that accumulate in an Alzheimer’s brain, and two years since they discovered that amyloid was a peptide—a protein fragment that came in different lengths. The researchers called the peptide beta amyloid and proposed that a genetic mutation causing its overproduction, would be found somewhere along chromosome 21, the chromosome that goes awry in Down Syndrome. The amyloid they had sequenced had come from Down’s patients, and by middle-age, most people with Down Syndrome experience Alzheimer’s-like symptoms, so it seemed logical that chromosome 21 would be implicated.