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Where do we stand with Alzheimer's disease?


A BETTER UNDERSTANDING of Alzheimer's disease is a high priority in a society that is demographically aging. This dreaded dementing disorder has been the subject of intensive study at Columbia and elsewhere since well before President Ronald Reagan's case enhanced public awareness of the disease. One logical inference from current research is that neither a single causal theory, a simple test, nor a "magic bullet" therapy is likely to help us master this enemy, but we are moving closer to being able to do something about it.

AD afflicts 4 million people in the United States and costs $100 billion annually. Columbia neuroepidemiologist Richard Mayeux is seeking links among genetic makeup, environmental factors, and disease development, with a practical goal in mind: identifying potentially modifiable risk factors. "We would like to delay the onset or progression of disease by five to 10 years. That would cut our spending on the disease in half," Mayeux says, emphasizing the emotional benefits to patients and families as well: "You've got to give people hope." He has begun a prospective study of 1,700 elderly people to determine whether genotype, education, smoking, head injury, family history, or other factors influence risk.

Recent research has elucidated some genetic causes of early-onset Alzheimer's, which strikes before age 60, but this form accounts for fewer than 5 percent of cases. A genetic risk factor for the more common late-onset form has also been discovered, offering the potential to "identify the largest number of people at risk of Alzheimer's," says Mayeux, director of the Sergievsky Center at Columbia. "We haven't had something of this magnitude to work on before."

Denis Evans, co-director of the Rush Alzheimer's Disease Center in Chicago, compares the progression of AD research to that for heart disease. A few decades ago, a heart disease epidemic was clearly in progress, but researchers hadn't determined what factors increased risk. Epidemiological studies beginning in the late 1940s clarified links between heart disease and risk factors such as smoking or high cholesterol levels. Now AD is reaching epidemic proportions, but the causes and risk factors are still largely unknown. "We really got serious as a society in the early 1980s" about Alzheimer's, Evans says. "Now we're progressing to risk factor studies."

First described in 1907, AD probably results from a variety of genetic and environmental factors leading to the same endpoints: dementia and pathological signs including loss of brain mass, tangles of fibrils within neurons, and plaques made up in part of an extracellular protein fragment called beta-amyloid. Debate rages over the cause of Alzheimer's, and the outcome will influence treatment strategies.

For years, the dominant theory has pointed to amyloid. "Amyloid is always present in disease," says Dale Schenk, director of neurobiology at California-based Athena Neurosciences. He argued for the amyloid hypothesis at a 1995 Society for Neuroscience debate, citing as further evidence a link between mutations in a gene coding for the amyloid precursor protein, which is cleaved to make b-amyloid, and the disease.

Others contend that amyloid is simply a marker for the disease, not its cause. "Dementia is caused by the loss of synapses in the cortex, and most of that loss is not related to amyloid," says Robert D. Terry, professor emeritus of neurosciences and pathology at the University of California at San Diego, who opposed the amyloid hypothesis in the debate. "You can have a lot of amyloid with no dementia," he says. "It's not specific to Alzheimer's disease."

Clues from amyloid deposition and genetic linkage studies have led researchers to some of the causes for early-onset Alzheimer's: mutations in genes on chromosomes 1, 14, and 21. These genes code for a variety of proteins, including the amyloid precursor protein.

Recently, Allen Roses and colleagues at Duke University jolted the research community by teasing out a susceptibility gene for late-onset Alzheimer's. Known as apoE, it codes for apolipoprotein E, a cholesterol-transporting protein expressed in the central nervous system and also implicated in cardiovascular disease. "If we understood what apoE potentially does in Alzheimer's disease, we could develop a treatment to reduce the biological effects," Mayeux says.

Certain alleles of apoE increase the risk of AD and lower the age of onset, speeding a natural process that would put all humans at risk if they lived long enough, according to Roses. In general, people who carry two copies of the apoE4 allele (one from each parent) are more likely to develop AD than those with the apoE2 or apoE3 forms. "We think that the metabolism of different apoE isoforms accounts for differences in the rate of onset," Roses says. The apoE has been linked to the formation of both plaques and tangles characteristic of AD.

While having two copies of apoE4 carries risks for members of many racial groups, Mayeux has found some differences for carriers of one apoE4 combined with another allele. He reported last year that African-Americans are less susceptible than other groups to the influence of a single copy of apoE4 and also that head trauma can increase the risk of AD in anyone with an apoE4 allele. In a northern Manhattan community, he found that elderly people with at least one apoE4 allele who also suffered a traumatic head injury were 10 times as likely as controls to develop AD. Having an apoE4 allele alone doubled the risk.

Other risk factors are surprisingly diverse, ranging from mood disorders to prose style. D.P. Devanand, a Columbia associate professor of clinical psychiatry, reported this year that elderly people with depression are twice as likely to develop AD and other forms of dementia. It is not yet clear whether depression is an early symptom of AD or increases susceptibility via another route, Devanand says.

Columbia neuropsychologist Yaakov Stern, working with Mayeux and others, has shown that people with higher educational or occupational attainment had a lower risk of AD and held symptoms at bay longer than their peers. A recent study adds a new twist, inversely correlating linguistic ability early in life with AD later. Researchers at the University of Kentucky studied writing samples taken at the average age of 22 from a group of School Sisters of Notre Dame. Nuns whose writing had a low density of ideas were more likely to develop AD.

This intriguing finding needs to be explored further, Mayeux says. "People have been suggesting for a while that the level of education, occupational achievement, and other sociocultural factors seem to have some role in Alzheimer's disease," he says. "Some people have a cognitive reserve that protects them." The suggestion that mental clarity may be a use-it-or-lose-it proposition carries useful common-sense implications for prevention, whether or not the causal debate is ever resolved.

CAROL BLANEY is a free-lance writer based in San Jose, Calif. She has been a science reporter for the Raleigh News and Observer and for the award-winning health quarterly Network.

PHOTO CREDIT: UPI/Bettmann, used with permission.

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