Reading Alzheimer’s markers
Effective treatments for Alzheimer’s disease appear several years away at best. But, in what could be considered a painful irony, scientists have become increasingly adept at spotting the illness in its earliest stages. Magnetic resonance imaging, PET scans, spinal fluid analyses and other techniques have enabled physicians to reliably detect the disease -- often years before symptoms appear.
These detection methods identify mild cognitive impairment, a condition that many scientists consider a high-risk precursor to Alzheimer’s disease. The impairment is marked by a pattern of forgetfulness that’s unusual for the person, though it doesn’t necessarily interfere with daily activities. Of the several million Americans thought to have the condition (the figure might be higher because it can be written off as common aging), roughly 15% advance to full-fledged Alzheimer’s every year. “Even since five years ago, there’s been a huge technical jump,” says Dr. William Jagust, a professor of public health and neuroscience at UC Berkeley. “I think for the first time, we have the idea that we might be able to predict what happens to normal older people who aren’t having symptoms -- to predict who among that group is destined to develop Alzheimer’s disease could be possible.”
Now it’s time to change the criteria for diagnosing Alzheimer’s, suggests an international group of 19 neurologists and researchers in the August issue of Lancet Neurology.
Currently, a clinical diagnosis of mild cognitive impairment is not enough to enroll a person into Alzheimer’s treatment studies, says paper coauthor Dr. Steven DeKosky, director of the Alzheimer’s Disease Research Center at the University of Pittsburgh. Physicians diagnose “probable” Alzheimer’s if a patient has suffered significant memory impairment that’s not attributable to other mental conditions. (The disease can be confirmed only after brain tissue analysis, traditionally performed during autopsy.)
The suggested guidelines propose that someone with early signs of cognitive impairment be considered an Alzheimer’s patient if brain scans or fluid tests have spotted the red flags. Under this revised scenario, DeKosky says, “We’d say you meet the criteria for Alzheimer’s disease. Let’s start treating you.”
The patient could then become a candidate for experimental therapies. Likewise, including more patients with preliminary Alzheimer’s in such studies could help to refine these treatments.
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Early detection
One of the most promising and accurate early detection methods is a PET scan technique designed by Dr. Gary Small, director of the UCLA Center on Aging, and his colleagues. The group created a chemical that sticks to plaques and tangles of tau and amyloid proteins in the brain long enough to be seen on PET scans. They are among the first to detect these clear signs of Alzheimer’s in living patients.
One of the group’s recent studies showed just how precise the scans are. In the Dec. 21, 2006, issue of the New England Journal of Medicine, Small and his colleagues reported that, based on brain images, they could distinguish a healthy person from someone with mild cognitive impairment, and someone with that condition from one with Alzheimer’s. The technique is being studied for commercial application, and Small says it could be available to patients in about five years.
MRI scans and spinal fluid tests also have proved promising at detecting early signs of Alzheimer’s. Using magnetic resonance images, researchers have linked a small hippocampus, which processes memory, to the cognitive decline associated with Alzheimer’s.
But because scientists can’t show that such decline actually causes the disease, they generally consider tau and amyloid levels to be more closely tied to Alzheimer’s. Besides, sometimes a small hippocampus doesn’t lead to any noticeable change in a person’s mental health.
And spinal tests, known as lumbar punctures, can measure the amounts of tau and amyloid-beta in the fluid at the base of the brain. In March 2006, a team of Swedish researchers reported that spinal fluid could be used to predict which patients with mild cognitive impairment would develop Alzheimer’s. Their six-year study of 137 impaired patients, published in Lancet Neurology, found that those who began the test with high tau and low amyloid levels were roughly 18 times as likely to advance to Alzheimer’s.
“I tell people to do a lumbar puncture,” DeKosky says of patients who come to him fearing they might be developing Alzheimer’s. “If you have a change in protein, you have an answer.”
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Genetic markers
Other researchers are trying to trace the roots of Alzheimer’s through genetic markers. If successful, a genetic test could indicate whether a person is at risk for Alzheimer’s decades before any signs show up in brain scans or fluid analyses.
In the 1990s, scientists discovered apolipoprotein E (ApoE), a gene linked with a high risk of Alzheimer’s. But not everyone with the high-risk variant of ApoE develops the disease -- and not everyone with the disease carries that variant -- so researchers have since looked for other major genetic indicators.
Recently many researchers have focused on a mutation of the gene SORL1, which appears to play a role in amyloid regulation and to increase the likelihood of developing full-blown Alzheimer’s. A study published in September in the Annals of Neurology extends that relationship to early Alzheimer’s, suggesting a link between mild cognitive impairment and low levels of the protein made by SORL1, called LR11.
How much LR11 a person makes “may ultimately be responsible for modifying the risk of developing Alzheimer’s disease,” says neurologist and study leader Dr. James Lah of Emory University. “If that’s true, it becomes a new and potentially important target for developing therapeutics.”
The researchers also found varying amounts of the protein among people with mild cognitive impairment, suggesting that different levels of risk exist even among those with the condition.
Meanwhile, geneticist Rudolph Tanzi of Massachusetts General Hospital and his colleague Dr. Lars Bertram have compiled a database of genes implicated in Alzheimer’s, weighing the importance of each based on the results of published studies. They reported some of their findings in the January issue of Nature Genetics and maintain a searchable database online at www.alzgene.org.
The researchers, who lead the Alzheimer’s Genome Project, aim to find the remaining genes linked to the disease by 2008. So far, says Tanzi, no gene comes even close to apolipoprotein E in terms of carrying a high risk for Alzheimer’s.
“If ApoE is David Ortiz,” he says, referring to the Major League slugger, “the next genes down would all be Little Leaguers.”
Regardless of the best way of diagnosing Alzheimer’s, researchers hope that by catching the disease early, they can target the illness at its most vulnerable state when treatments do emerge. Perhaps they’ll even be able to break down tau tangles and amyloid plaques before they interfere with the brain’s normal functioning.
By the time a patient is functioning abnormally, physicians say, the disease is probably too advanced to treat. “We want to protect the healthy brain, rather than repair one that’s diseased,” Small says.
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Awaiting new treatments
Without available treatment, some people consider an early Alzheimer’s diagnosis unnecessarily alarming to patients or families. But such knowledge is critical so that “when medications are available, we know who to go after,” says Dr. Steven DeKosky, director of the Alzheimer’s Disease Research Center at the University of Pittsburgh.
After all, most major pharmaceutical companies are researching Alzheimer’s treatments. Some current drugs, such as memantine and cholinesterase inhibitors, can soften Alzheimer’s symptoms but don’t actually slow the onset of the disease. An ideal therapy would halt amyloid-beta production, or help the brain clear the protein before it built up into damaging plaques.
Some recent studies have shown that common food ingredients might have some therapeutic powers.
In a July 31 issue of Proceedings of the National Academy of Sciences, researchers led by Dr. Milan Fiala of the UCLA School of Medicine reported that a chemical common in curry powder helped prevent amyloid-beta plaque buildup in cells from blood samples of Alzheimer’s patients. Later this year, DeKosky will compile results of human research investigating whether ginkgo could serve as an effective Alzheimer’s deterrent.
If the findings are positive, DeKosky says, “wouldn’t you like to know that you could detect people early?”
“Forewarned is forearmed,” he says.
-- Eric Jaffe
