- The Washington Times - Saturday, May 24, 2003

Researchers who recently found a new genetic link to autism are now trying to find the genes that may increase the risk for the most common form of Alzheimer’s disease, which is destroying the brains of the elderly. William Scott, associate professor of research in Duke University’s Center for Human Genetics, who is involved in the Alzheimer’s research, says it has long been recognized there are “three genes whose mutations cause inheritable early onset Alzheimer’s” in patients before the age of 50. “But those cases represent less than 2 percent of all [those with] Alzheimer’s,” he said in an interview.

Mr. Scott said his supervisor, Dr. Margaret Pericak-Vance, who led the autism study, discovered a fourth gene about a decade ago that substantially increased the risk of late-onset Alzheimer’s, which typically first strikes people in their 60s or older. “That’s called the APOE [apolipoprotein E] gene, and we’re now trying to find other genes that have the same effect as APOE. … We’re trying to find genes that look like they increase the risk for the most common, late-onset form of Alzheimer’s,” Mr. Scott said.

The Duke team’s research is focusing on small American families that have multiple cases of Alzheimer’s. “We’re looking at genes which the affected people have in common,” said Mr. Scott, who added that the most suspected genes are on chromosomes 9, 10 and 12. The APOE gene is on chromosome 19.

Numerous researchers are trying to find the cause of Alzheimer’s, given the prevalence of the debilitating and fatal disease. Some researchers have even called it an epidemic.

The United States today has an unprecedented 4.2 million persons who are aged 85 or older, and it is estimated as many as half of them have Alzheimer’s.

These disturbing numbers come from the National Institute on Aging, the Alzheimer’s Association and other organizations that study Alzheimer’s, a progressive, degenerative brain disease that inevitably leads to complete loss of mental function and death.

A national epidemic

At least 4 million Americans now have the debilitating disease, and that total could climb to 14 million by 2050, if a prevention or cure is not found.

“Fourteen million is the number we’re using, which was based on the 1990 census. It will go up a little bit, based on the 2000 census,” Bill Thies, vice president of medical science and scientific affairs for the Chicago-based Alzheimer’s Association, said in an interview.

“But it probably doesn’t matter if it’s 14 million or 16 million or 20 million. The numbers are going to bankrupt the health care system and overwhelm care-giving resources,” Mr. Thies said.

Alzheimer’s is already costing $100 billion a year in “direct and indirect costs,” according to Neil Buchholtz, chief of the Dementias of Aging Branch of the National Institute on Aging.

Age is the main risk factor for Alzheimer’s. Hence, the number of cases is expected to rise sharply in correlation with the dramatic increase in the U.S. senior population.

That increase in America’s elderly is already under way, particularly at the oldest age levels. Between 1990 and 2000, the number of Americans ages 85 to 95 grew by 38 percent, according to the World Almanac.

That compares with a 12 percent jump during the same period for the overall U.S. senior population, or those aged 65 and over.

During that same decade, the increase of those aged 90 to 94 climbed nearly 45 percent. Those aged 95 and older rose almost 35 percent between 1990 and 2000.

A spokeswoman for the National Institute on Aging, the country’s primary federal agency researching Alzheimer’s, says research indicates between 40 percent and 50 percent of those age 85 or older have the illness.

The Alzheimer’s Association, a private organization that promotes Alzheimer’s research and offers support for patients who suffer from the disease and their families, says as many as 10 percent of Americans age 65 and older have Alzheimer’s, and it puts the proportion of Alzheimer’s patients age 85 and over at “nearly 50 percent.”

‘Nerve cells die’

So while it is encouraging that many Americans are living longer, it is disturbing that so many of them are spending their final years unable to recognize family members or friends, learn new things, perform routine tasks, engage in meaningful conversation, or even talk at all, because they’ve been stricken with Alzheimer’s.

As quickly as a person tells an Alzheimer’s patient something, the patient has forgotten it. The memory losses are linked to the breakdown of the connection between nerve cells in the brain and the fact that Alzheimer’s gradually, but relentlessly, destroys a patient’s brain cells.

“The nerve cells die. The connections between nerve cells die,” Mr. Buchholtz said.

An Alzheimer’s patient may be able to recall experiences that occurred during childhood, but the patient is not likely to remember an event from his immediate or recent past.

Just as there is much uncertainty as to what causes Alzheimer’s, no one is sure why patients with the disorder often can retain old memories. “It’s possible these older memories are laid down so much longer, it’s harder to get rid of them … yet Alzheimer’s patients are unable to store new memories,” Mr. Buchholtz said.

He added: “We think of Alzheimer’s as a problem of memory loss, but it’s also a problem of aggression, sleep disorders, agitation and patients wandering all night.”

Those problems, Mr. Buchholtz said, force many families to put loved ones with Alzheimer’s in nursing homes. It is estimated about half of all Americans in nursing homes today have Alzheimer’s.

Asked if such a life is acceptable for people who should be enjoying extended longevity, Mr. Thies replied: “The number getting Alzheimer’s disease is clearly not acceptable. … That’s why we have a solid commitment in saying this is not the way we want the world to be.”

Mr. Buchholtz agreed. “Alzheimer’s is a major public health issue,” he said.

That’s why the Alzheimer’s Association, the National Institute on Aging, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and other public and private groups are funding major Alzheimer’s research, which recently has been showing promise.

A person will live with Alzheimer’s for an average of eight years — some patients for as few as three and others for as many as 20 years or more — from the onset of symptoms. Alzheimer’s accounts for 70 percent of all those suffering from dementia, an umbrella term used to describe a decline in thinking skills.

Other disorders that can cause dementia include Parkinson’s disease, Huntington’s disease and Creutzfeldt-Jacob disease. The latter is the human form of mad cow disease, which causes holes in the brain.

Patients with Alzheimer’s or another less-common type of dementia become disoriented and paranoid, hiding possessions in bizarre places and eventually not having a clue as to where they left them. In the earlier stages, patients write themselves notes to remind them of things they have to do, and they are apt to get lost even in familiar settings.

During his unsuccessful presidential campaign in 2000, Sen. John McCain, Arizona Republican, alienated advocates of Alzheimer’s patients when he joked that people with the disease have an advantage at Easter, as they get to hide their own eggs.

Alzheimer’s patients basically lose their personalities and experience behavioral problems such as agitation, anxiety, delusions and hallucinations. An Alzheimer’s patient may seem content one minute but start crying the next for no apparent reason.

It’s not unusual for an agitated Alzheimer’s patient to completely disrobe and try to run away from caregivers.

“Seventy percent of Alzheimer’s patients are wanderers. Here in the greater Washington area two Alzheimer’s patients recently wandered from home and were found dead. Fifty percent are found dead if they are not located within 24 hours,” said Cindy Schelhorn, spokeswoman for the National Capital Area Chapter of the Alzheimer’s Association.

Unnoticed for so long

Most Americans probably think Alzheimer’s disease is a relatively new phenomenon, because they did not start hearing about it until the 1970s or early 1980s.

In fact, the first case of Alzheimer’s was diagnosed in 1906 by a German neurologist, Dr. Alois Alzheimer. The patient was a 47-year-old woman with dementia. In an autopsy of her brain, Dr. Alzheimer discovered two kinds of abnormal structures that are now recognized as hallmarks of Alzheimer’s disease: amyloid plaques and neurofibrillary tangles.

Amyloid plaque is a clump of pieces of dead nerve cells containing a gummy, insoluble substance called amyloid, which is believed to be responsible for much of the neuron destruction.

Neurofibrillary tangles are tightly twisted strands of equally gummy and insoluble proteins inside neurons. The structural aberrations found in the brains of Alzheimer’s patients are commonly referred to as “tangles and plaques.”

Mr. Thies said that Alzheimer’s went largely unnoticed for most of the 20th century because during that period doctors viewed the disease as a rare disorder that largely affected those age 50 or under.

Old people suffering memory loss or other cognitive impairment were thought to be experiencing “normal senility,” an effect of “normal aging,” an Alzheimer’s Association spokeswoman said.

Mr. Thies put it this way: “It was thought Alzheimer’s occurred in young people and that everybody got fuzzy as they got older. But then they started noticing that the pathology of those known to have Alzheimer’s was the same” as those of elderly people who had experienced serious mental difficulties.

In short, both groups had Alzheimer’s.

Mr. Thies noted that this was not the first time that a major killer disorder was initially mischaracterized as rare. “In the mid-1790s, when there was the first description of a myocardial infarction, or heart attack, it was said the disorder was really rare and only occurs in ‘old people over age 50,’” he said. For decades, heart disease has been this country’s number one killer.

“As we eliminated diseases that kill people at young ages, we exposed them to other diseases” in their later years, Mr. Thies said.

One of those most involved in making computer projections of the incidence of Alzheimer’s is Dr. Dennis Evans, professor of medicine at the Rush-Presbyterian-St. Luke’s Medical Center in Chicago.

He said his best estimate, based on census data, is that there were 4.5 million Alzheimer’s patients in the United States in 2000 and that there will be 13.2 million by 2050, unless there is a major medical breakthrough.

However, Dr. Evans says that figure could be as low as 11.3 million or as high as 16 million by midcentury.

“I don’t want those estimates to come true, just because people are living longer. That’s a heck of a price to pay. Our interest is in trying to do something about this illness. We all want to make these estimates obsolete or irrelevant,” Dr. Evans said in an interview.

The Alzheimer’s Association says it is a “myth” that memory loss is a natural part of aging. “Whether memory naturally declines to some extent remains an open question. Many people feel their memory becomes less sharp as they grow older, but determining whether there is any scientific basis for this belief is a research challenge still being addressed,” the association said in a statement, adding:

“Experts now recognize severe memory loss as a symptom of serious illness.”

Searching for a cure

At this time, there is no medical treatment to cure or stop the advance of Alzheimer’s. The Alzheimer’s Association says the four drugs the U.S. Food and Drug Administration has approved for Alzheimer’s patients — tacrine, donepezil, rivastigmine and galantamine — may temporarily improve or stabilize memory and thinking skills in some people.

The association also stresses that Alzheimer’s is a fatal disease. While it begins with the destruction of cells in regions of the brain that are important for memory, the eventual loss of cells in other regions of the brain leads to the failure of other essential systems in the body.

As grim as the outlook for the spread of Alzheimer’s is today, extensive research is under way, and some of it looks promising.

A wide variety of treatment strategies are in the pipeline. The one causing the greatest excitement is the effort to eliminate the beta-amyloid protein from the brain or to reduce its production, Mr. Buchholtz and Dr. Evans said.

But Mr. Buchholtz said researchers had a setback several years ago in human trials with a vaccine to prevent the amyloid plaque from building up. “The results of mouse and primate studies looked good. But in a second human trial, [some subjects] got brain inflammation, so the trial had to be stopped,” he said.

Other drugs, compounds or hormones being tested as possible Alzheimer’s treatments include B vitamins, folic acid, anti-inflammatory drugs, free radicals, anti-oxidants, estrogen, and so-called “statin” drugs used to lower cholesterol.

Mr. Buchholtz said “many more women than men” have Alzheimer’s, and scientists are trying to determine whether that is solely because women live longer than men. The gap between the life expectancy of women and men is now 5.4 years.

Mr. Buchholtz said “some studies showed a slightly increased” incidence of Alzheimer’s in women than men, after controlling for longevity. “So they could be more susceptible,” he said.

“In the next five to 10 years, we will have many drugs to delay the progress of Alzheimer’s,” Mr. Buchholtz predicts.

One experimental tool that looks promising, and which was announced just recently, builds on the imaging machines such as PET scans that are sometimes used on people with suspected Alzheimer’s. The machines now in use can show whether parts of the brain have shrunk or work slowly.

But in order to view the “tangles and plaques” that constitute Alzheimer’s, one needed to wait for a brain autopsy.

Some researchers today are using PET scans that allow them to see those tell-tale proteins in the brains of living Alzheimer’s patients. The scans light up the plaque so scientists can see it creeping across the brain.

“This is not ready for prime time yet,” Mr. Buchholtz said.

But he said having the ability “to look at plaque in the brains of living people” could be extremely beneficial. “You can monitor drugs that target plaque to see if they get rid of it,” Mr. Buchholtz said.

A research team at the University of California in Los Angeles plans to use the newly developed brain scans in a study to determine if common anti-inflammatory drugs, such as aspirin, ibuprofen, and sodium naproxin, dissolve some of the plaque in the brains of early Alzheimer’s patients.

According to a report published recently in the journal Neuroscience the researchers said that such pain-killing medications helped to dissolve plaque in a test-tube study they conducted.

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