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Families With Inherited Alzheimer's Gene Grapple With Whether To Test

As a boy, Gary Reiswig would take his grandfather by the hand and guide him on walks around the family farm in western Oklahoma. At 5, Gary knew to avoid the prairie dog town, fearful that his grandfather might stumble over one of the holes that the rodents burrowed into the grassy plain.

Occasionally, his grandfather would stop. His eyes took on an eerie stare that spoke of an empty place -- one that once was filled with memories, laughter and toil.

In 1945, nobody knew that Gary's grandfather had a rare form of Alzheimer's disease that would strike 10 of Gary's 14 aunts and uncles, his father and his only brother and sister in the prime of their lives.

Gary's family has dominantly inherited Alzheimer's disease. It is rare, and it afflicts the young. In his family, symptoms can appear in the early 40s.
Story: Predicting Alzheimer's: Would you want to know?

This inherited form of Alzheimer's is caused by mutations in one of three genes: amyloid precursor protein, presenilin 1 or presenilin 2. It is the only form of Alzheimer's for which there is a diagnostic test that can predict with certainty whether Alzheimer's will ensue.

That may change. Researchers, patient advocates and policy makers are pushing for earlier testing of Alzheimer's, in part because it will help the search for a cure. That means more people could find out if they will succumb to the disease.

But without a treatment or a cure, would people want to know?

Surprisingly, yes, said Dr. Robert Blendon, professor of health policy and political analysis at the Harvard School of Public Health.

Blendon conducted a survey of 2,678 adults from five countries that was released on Wednesday at the Alzheimer's Association International Conference in Paris. About two thirds of respondents said they were likely to get a test to predict whether they would get Alzheimer's before any symptoms appeared.

Some 35.6 million people worldwide have Alzheimer's, the most common form of dementia. Drugs only help symptoms; none can arrest Alzheimer's, which costs $604 billion a year globally to treat.

All of the drugs that have been tried in people with advanced dementia have failed to slow the disease, and many experts think the reason is that they were tried on people who were too far gone.

Some people who know Alzheimer's may lie in wait make different life choices. They take more extravagant vacations, they put their finances in order earlier than many other people. They even may use a surrogate parent instead of taking a chance of passing on the disease to a new generation.

Early prevention, early treatment
There are no tests that can detect Alzheimer's before symptoms appear, but researchers are getting closer.

Eli Lilly and Co is seeking U.S. Food and Drug Administration approval to sell an Alzheimer's imaging agent for use with positron emission tomography, or PET, scans to help doctors rule out Alzheimer's.

In January, an advisory panel to the FDA said it would consider approving the compound, but it wants the company to develop a training program to ensure radiologists can read brain scans using the compound consistently.

Lilly acquired the drug through its recent purchase of Avid Radiopharmaceuticals Inc, which has been leading a three-way race for such imaging agents with General Electric Co and Bayer AG.

The agents could have a potential global market of anywhere from $1 billion to $5 billion, according to these companies.

Scientists are also looking for signals of Alzheimer's in cerebrospinal fluid. These tests look for two Alzheimer's-related proteins: beta amyloid, which forms sticky plaques in the brain, and tau, a marker of cell damage. Low levels of beta amyloid in spinal fluid suggest it may be accumulating in the brain, and high tau levels suggest nerve cell death.

Some doctors already test for this to confirm that Alzheimer's has caused a person's dementia.

Encouraged by these steps, National Institute on Aging, part of the National Institutes of Health, and the Alzheimer's Association in April revised the diagnostic criteria for Alzheimer's for the first time in 27 years to recognize mild cognitive impairment as a precursor to the disease.

They also added a new research category called preclinical Alzheimer's, the earliest stage of the disease when clumps of amyloid start to form in the brains of people who are otherwise healthy.

This stage, which occurs some 10 years before dementia sets in, is seen as the best place to intervene. It is why new imaging agents for PET scans, spinal fluid tests and so-called biomarkers that predict Alzheimer's are becoming so important to researchers and drug companies.

"The guidelines portend a lot more than just how to diagnose Alzheimer's today," said Dr. Daniel Skovronsky, founder and chief executive of Avid Radiopharmaceuticals.

"I think many people now have a sense of hope that some day we can make Alzheimer's a preventable disease, and that is through early prevention and early treatment," he said.

Part of the cure
Gary was 25 when he found out his father had Alzheimer's, and he lived with the possibility that he might develop the disease until he was 57. That is when he learned he did not inherit the gene.

His family already saw the grim results of the disease. Gary's grandfather, at age 53, veered into the path of a freight train in 1936. The accident killed his grandmother; his grandfather survived with a few stitches and lived another 10 years.

"My family attributed his disease and forgetfulness to his grief over this accident," Gary said. It was only later, when the next generation began to suffer the same symptoms, that one of his aunts began to suspect something was terribly wrong.

Gary's family and 11 other North American families have mutations in the presenilin 2 gene. They are descendants of Germans who settled in two villages in the Volga region of Russia in the 1760s, and later settled in the United States in the late 19th and early 20th centuries.

Their disease is autosomal dominant, meaning children only need to get one abnormal gene from either parent to inherit the disease, and each child has a 50/50 chance of getting it.

This form of Alzheimer's comprises about 1 percent of the cases of Alzheimer's worldwide.

"If you have that mutation, so far as we know, you will in fact get that disease," Gary said.

And because of that guarantee, Gary's family and others may soon lead the way to a cure for the disease.

Trial studying progress
A clinical trial known as the Dominantly Inherited Alzheimer's Network, or DIAN, is studying families with inherited forms of Alzheimer's to learn more about how the disease progresses.

Funded by a grant from the National Institute on Aging in 2008, DIAN has the largest and most extensive worldwide research network investigating dominantly inherited Alzheimer's, with sites in the United States, Britain and Australia.

Initial results from the study presented at the Alzheimer's Association meeting suggest inherited forms of the disease can be detected as many as 20 years before problems with memory and thinking develop.

They found that, as with people with more common Alzheimer's, people who develop early onset disease experience a drop in amyloid in their spinal fluid and an increase in tau some 20 years before their symptoms appear.

The findings suggest that there is a common pathway between inherited Alzheimer's and late-onset Alzheimer's, said Dr. Randall Bateman of Washington University School of Medicine in St. Louis, who is an associate director of the study.

"That is the pathway we want to treat. If we can interfere with that, we can hopefully prevent Alzheimer's disease," he said.

Drug companies are being selected to test their experimental medicines on these study volunteers because if they have the gene, they are certain to get Alzheimer's.

"It's a huge opportunity," said Dr. Rachel Schindler, an Alzheimer's disease expert at Pfizer Inc, which is developing the drug bapineuzumab with Johnson & Johnson, which is now in late-stage clinical trials.

"It's a window into how early we really can detect the changes related to Alzheimer's disease. Without that window, you'd have to study hundreds of people over a long period of time because only a few of them would end up developing the disease," Schindler said.

If scientists can understand the disease, they can apply much of what they learn to late-onset Alzheimer's, she said.

People in the study are eager to participate in the drug trials, Bateman said. "They are desperate to have treatments for their families."

Marty Reiswig, a 32-year-old minister living near Denver, found out about the study from his brother Matt. Matt told Marty that he had to read a book about the family's disease by Gary Reiswig -- their father's cousin.

After reading the book, "The Thousand Mile Stare: One Family's Journey through the Struggle and Science of Alzheimer's," the brothers agreed that their family would make perfect "lab rats," Marty said.

That is because people in his family, unlike most people who get Alzheimer's, know it's coming, he said.

Marty undergoes annual lumbar punctures to have his spinal fluid checked for levels of amyloid and tau -- the proteins that help predict Alzheimer's progression -- and because he has no symptoms, he has a battery of memory tests every three years.

"Because I am a child of an affected early onset Alzheimer's person, they want to study my mental health progress," Marty said.

Marty's and Matt's father Lawrence is also part of the study.

Marty says he relishes his visits with Dr. Bateman, and loves to pepper him with questions about the study.

In one recent visit, he got some good news.

"I was lying in bed with lumbar puncture in my back, talking to Dr. Bateman," Marty recalled. "He said, 'I think some time in the next 12 months, there is a very good possibility we might be doing clinical trials with you to find drugs to prevent the onset of Alzheimer's.'"

Marty said he lay in the hospital bed and wept.

"My dad was across from me in the hospital room and we had to control ourselves. That this terrible thing could possibly sort of vanish... that was just a huge relief for us."

"That was thrilling," said Lawrence, who is 58 and just starting to show signs of Alzheimer's.

"He is still very functioning, but worsening," Marty says of his father, who lives in Greeley, Colorado, with his mother Bonnie. "It has most affected his speech."

Lawrence says it takes about five minutes to get himself a bowl of cold cereal and a spoon in the mornings, largely because he gets distracted so often.

"He has a fantastic attitude. He laughs at himself and allows others to laugh about his mistakes," Marty said. "Here he is, faced with this cruel, slow ending to his life, and the embarrassment factor is huge."

When people are in their 90's and make social gaffes, people tend to excuse them, Marty said. "'When you make those same social mistakes at age 58, the people who know what is going on give you grace, but everyone else wonders what is wrong with you.'"

Anxiety over future
Despite all the hope, some doctors and social workers who treat Alzheimer's and care for their families say the push for early testing is premature.

"The tests are so inaccurate at this point that I don't know what the value is other than to create a lot of anxiety," said Debra Greenberg, geriatrics social worker at Montefiore Medical Center in New York.

Greenberg is skeptical of polls showing strong interest in early testing, especially when they are done among people who are young and healthy.

"I think what you decide when you are a healthy and well 40-year-old is very different from what you decide when you are older," she said. "You are not that 40-year-old when this happens to you."

Other Alzheimer's experts see value in early diagnosis.

"We think right now, today, there is a clear benefit of an early diagnosis," says Bill Thies, chief scientific officer of the Alzheimer's Association, whose group has been a proponent of early diagnostics for many years.

One reason is that studies suggest people who understand the course of Alzheimer's disease and what to expect from it cope better with the disease.

"This is true of patients and caregivers," Thies said.

Thies said an early diagnosis also helps with end-of-life decisions, allowing the patient to plan their care instead of leaving these decisions to others.

It also leaves time for financial planning.

"If you know you're starting down that path, you know to get your affairs in order. You take care of family issues so it won't be a big surprise later when it gets worse," said Dr. Creighton Phelps, director of the Alzheimer's Disease Center Programs in the National Institute on Aging's division of neuroscience.

But Blendon of Harvard worries about raising expectations by testing people and not offering treatments.

"For people who are so used to hope that medical science can push the darkness away here, they could be disappointed."

And there are good reasons not to get tested.

Marty has decided not to find out his gene status. He is afraid that knowing he has the gene might jeopardize his long-term care insurance.

"My wife and I have chosen to live as if I have it anyway," said Marty, who has a 5-year-old girl and 3-year-old boy.

The decision over whether to have children who could suffer the same genetic risk is especially touchy. Marty said his grandmother Ester, who was instrumental in helping bring the family's genetic disease to light, urged members of the family not to have children.

"Personally, I'm glad that no one followed that rule," he said. "I've been given a life by my parents and the good Lord. I love my wife. We both knew the genetic risk, but it is a very natural thing -- we wanted to have kids and love them and raise them, no matter what their future."

Every five years, they plan a big vacation. The last one was to Italy.

"I don't know how long I have. It drives me to seize the day because I could get Alzheimer's symptoms as early as my mid-40s, and here I am at 32."

Gary says it is common among the younger members of his family not to get tested. "They say, 'maybe when I'm 50,' but I don't want to know now."

Gary had no idea of the weight of his burden of living with the threat of Alzheimer's until the day he found out he did not inherit the gene.

"It was joyous relief. I just wanted to sing. And then, there was just this horrible weight of grief and sadness because of not only my brother and sister, but all of the other members of my family I have seen who have lived through this."


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