Friday, June 15, 2012

An Alzheimer’s Gene - One Family’s Saga -

It seemed as if it would be a perfectly ordinary occasion, that hot August day in 1959. Three generations of a large Oklahoma family gathered at a studio in nearby Perryton, Tex., to have a photo taken of the elders, 14 siblings ranging in age from 29 to 52. Afterward, everyone went to a nearby park for a picnic.

Among the group were two cousins, Doug Whitney, who was 10, and Gary Reiswig, who was 19. Doug's mother and Gary's father were brother and sister. Doug does not remember any details of that day, but Gary says he can never forget it. His father, and some of his aunts and uncles, just did not seem right. They stared blankly. They were confused, smiling and nodding, even though it seemed as if they weren't really following the conversation.

Seeing them like that reminded Gary of what his grandfather had been like years before. In 1936, at the age of 53, his grandfather was driving with his grandmother and inexplicably steered into the path of a train. He survived, but his wife did not. Over the next decade, he grew more and more confused. By the time he died at 63, he was unable to speak, unable to care for himself, unable to find his way around his house. Now here were the first signs of what looked like the same condition in several of his children.

"We were looking at the grimness face to face," Gary says. "After that, we gradually stopped getting together."

It was the start of a long decline for Gary's father and his siblings. Their memories became worse, their judgment faltered, they were disoriented. Then one day in 1963, Gary, who was living in Illinois at the time, went with his mother to take his father to a doctor in Oklahoma City. The doctor had recently examined his father's brother, and after administering some simple memory tests and hearing about the rest of the family, concluded that he probably had Alzheimer's disease. Gary and his mother took his father in for the same exam, and the doctor confirmed Gary's fears.

Gary's mother wanted to keep his father's condition a secret and asked Gary to tell no one. But his uncle's wife, Aunt Ester May, wanted to let everyone in the extended family know. Most reacted the way Gary's mother had — they wanted to keep the information to themselves.

When Doug first heard the news, he hoped his mother, Mildred Whitney, might escape the terrible illness, and for a few years she seemed fine. But on Thanksgiving Day 1971, Mildred, who was then 50 and never used recipes, could not remember how to make her famous pumpkin pie.

That was the beginning of her precipitous fall. Five years later, after she lost her ability to walk, or speak, or recognize her own children, she died. In the end, 10 of those 14 brothers and sisters developed Alzheimer's, showing symptoms, on average, at around age 50. The family, once close, soon scattered, each descendant of the 14 privately finding a way to live with the possibility that he or she could be next.

More than five decades later, many of these relatives have come together to be part of a large international study of families who carry an Alzheimer's gene. The study, known as DIAN (for Dominantly Inherited Alzheimer Network), involves more than 260 people in the United States, Britain and Australia and includes at least 10 members of Doug and Gary's family. Since 2008, researchers have been monitoring the brains of subjects who have mutations in any of three genes that cause Alzheimer's to see how the disease develops before symptoms occur. By early next year, DIAN researchers plan to begin a new phase. Subjects will receive one of three experimental drugs that the researchers hope will slow or stop the disease in people otherwise destined to get it. (A similar study is expected to start around the same time in Colombia, testing one drug in a large extended family that carries a mutation in one gene that causes Alzheimer's.)

Though as much as 99 percent of all Alzheimer's cases are not a result of a known genetic mutation, researchers have determined that the best place to find a treatment or cure for the disease is to study those who possess a mutation that causes it. It's a method that has worked for other diseases. Statins, the drugs that are broadly prescribed to block the body's cholesterol synthesis, were first found effective in studies of people who inherited a rare gene that led to severe and early heart disease.

Alzheimer's is the sixth leading cause of death in this country, and is the only disease among the 10 deadliest that cannot be prevented, slowed or cured. But DIAN investigators say that within a decade there could be a drug that staves off brain destruction and death.

This sense of optimism has been a long time coming. In 1901, a German psychiatrist, Alois Alzheimer, first noted the disease when he described the case of a 51-year-old woman named Auguste Deter. "She sits on the bed with a helpless expression," Alzheimer wrote. "What is your name? Auguste. Your husband? Ah, my husband. She looks as if she didn't understand the question."

Five years later, when Auguste Deter died, Alzheimer examined her brain. It was the color of sandpaper and the texture of tofu, like every other brain. But there the similarities ended. Deter's brain was shriveled and flecked with tiny particles that stuck to it like barnacles. No one had ever seen such a thing before in any brain.

Pathologists now recognize that the particles are deposits of a protein fragment, beta amyloid, that accumulates in brains with Alzheimer's and is a hallmark of the disease. Alzheimer also noticed something else in Deter's brain. Inside her ruined brain cells were tangles: grotesquely twisted ropes of a protein now known as tau. They are not unique to Alzheimer's — they show up in the course of aging and in other degenerative brain diseases, including Parkinson's and Pick's disease, a rare form of dementia whose distinguishing symptoms include erratic and inappropriate behavior. Alzheimer speculated that the tangles in the brain cells were grim signs of the brain's destruction. But what caused that destruction was a mystery. "All in all we have to face a peculiar disease process," Alzheimer wrote.

There matters stood until the latter part of the 20th century. A leading Alzheimer's researcher, Paul Aisen of the University of California, San Diego, told me that when he was in medical school in the late 1970s, his instructors never talked about Alzheimer's. There was little to say other than that it was a degenerative brain disease with no known cause and no effective treatment. Scientists just did not have the tools to figure out what was going wrong in the brains of these people, or why.

All anyone knew was that the disease followed a relentless path, starting with symptoms so subtle they could be dismissed as normal carelessness or inattentiveness. A person would forget what was just said, or miss an appointment, or maybe become confused driving home one day. Gradually those small memory lapses would progress until the person, now wearing a blank stare, would no longer recognize family members and would be unable to eat or use a bathroom. At autopsy, the brain would be ruined, shrunken and peppered with plaques.

Rudolph Tanzi, a professor of neurology and an Alzheimer's researcher at Harvard University, explained what it was like for researchers back then to look at an Alzheimer's brain and try to figure out what caused the devastation. Imagine, he says, that you are an alien from another planet who has never heard of football. You go into a stadium at 5 o'clock, after a game has been played, and see trash in the stands, a littered field, torn turf. How, he asks, could you figure out that it was all caused by a football game? "For decades, that was where we were in trying to figure out the cause of Alzheimer's disease," Tanzi says.

But as molecular biology advanced, scientists realized that if they could study large families in whom the disease seemed to be inherited, they might be able to hunt down a gene that caused Alzheimer's and understand what it did. The difficulty was finding these families and persuading them to participate in the research. A breakthrough came in the late 1980s when a woman who lived in Nottingham, England, contacted a team of Alzheimer's researchers at St. Mary's Hospital in London, led by John Hardy, and asked if they wanted to study her family. Alzheimer's had appeared in three generations, she said, and her father was one of 10 children, 5 of whom developed the disease.

In the English family, the pattern of inheritance seemed clear — the child of someone with the disease had a fifty-fifty chance of developing Alzheimer's — which meant that it was very likely that a gene was causing the disease. By comparing the DNA sequences of family members who developed Alzheimer's to the sequences of those who did not develop the disease, the researchers discovered that the family's disease was caused by a mutated gene on chromosome 21. Everyone in the family who had Alzheimer's had that mutated gene. No one who escaped the disease had the mutation. And all who inherited the mutated gene eventually got Alzheimer's. There were no exceptions.

"Sometimes in science, you generate the information and the data gradually," Alison Goate, who was a young geneticist in the research group, told me. "This was like, boom, a eureka moment." She says she remembers thinking, "I am the first person to see a cause of Alzheimer's disease."

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Neuroscience: The mind reader : Nature News & Comment

Adrian Owen still gets animated when he talks about patient 23. The patient was only 24 years old when his life was devastated by a car accident. Alive but unresponsive, he had been languishing in what neurologists refer to as a vegetative state for five years, when Owen, a neuro-scientist then at the University of Cambridge, UK, and his colleagues at the University of Li├Ęge in Belgium, put him into a functional magnetic resonance imaging (fMRI) machine and started asking him questions.

Incredibly, he provided answers. A change in blood flow to certain parts of the man's injured brain convinced Owen that patient 23 was conscious and able to communicate. It was the first time that anyone had exchanged information with someone in a vegetative state.

Patients in these states have emerged from a coma and seem awake. Some parts of their brains function, and they may be able to grind their teeth, grimace or make random eye movements. They also have sleep–wake cycles. But they show no awareness of their surroundings, and doctors have assumed that the parts of the brain needed for cognition, perception, memory and intention are fundamentally damaged. They are usually written off as lost.

Owen's discovery1, reported in 2010, caused a media furore. Medical ethicist Joseph Fins and neurologist Nicholas Schiff, both at Weill Cornell Medical College in New York, called it a "potential game changer for clinical practice"2. The University of Western Ontario in London, Canada, soon lured Owen away from Cambridge with Can$20 million (US$19.5 million) in funding to make the techniques more reliable, cheaper, more accurate and more portable — all of which Owen considers essential if he is to help some of the hundreds of thousands of people worldwide in vegetative states. "It's hard to open up a channel of communication with a patient and then not be able to follow up immediately with a tool for them and their families to be able to do this routinely," he says.

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