Kassie Rose, 30 years old, faces a frightening prospect: if a genetic coin toss fails to go her way, she could lose her mind within a decade or two. A mutation that causes Alzheimer’s disease runs in her family, the DeMoes of North Dakota. The odds of any DeMoe harboring the mutation are 50–50, and if the mutation is present, the chances of developing early-onset Alzheimer’s—the type that erodes memory before age 65—are 100 percent.
Five of the six DeMoe siblings—Rose’s father and her aunts and uncles—have the mutation. One man is in a nursing home in his mid-50s; a second, younger, is on his way. A sister in her late 40s is already noticing her first symptoms. The next generation is tortured with the decision of whether to get tested. Rose, for now, chooses not to know. After all, she is unlikely to benefit much from the information: Alzheimer’s remains incurable and, largely, unpreventable as well.
But the ability to predict the devastating disease—a disorder that robs about five million people in the U.S. of their memory, identity and ability to function—is of great benefit to science and the quest to find a cure for the ailment. For example, a long-range disease forecast offers scientists the opportunity to watch as the disease progresses from its earliest stages and to link changes in the brain (using imaging techniques) to cognitive problems as a way of tracing the most important biological underpinnings of Alzheimer’s.
Only 1 percent of all cases are caused by inherited mutations such as the one that pervades the DeMoe family tree. But on the horizon are novel tests for the much more common late-onset form of Alzheimer’s, which is thought to result from multiple interacting genetic and environmental factors, many of which are unknown. Beyond issuing a mere yes-no forecast, the new tests help to paint a picture of the pathology that is otherwise only visible at autopsy, yielding a wealth of biological information that could be used to develop and test antidementia drugs.
And although the new technologies are still experimental, researchers hope they will be able to definitively diagnose Alzheimer’s in the living and perhaps even predict when the confusion and loss of memory will begin so that patients and their families can prepare for the ordeal of living with Alzheimer’s. In addition, when—or if—an effective remedy is available, neurologists could begin treatment before the symptoms appear, maybe halting the advance of the disease so its victims can lead long, normal lives and turning the disorder into a mild chronic affliction. Doctors might also target drugs to particular pathologies as they pop up in the brain. Indeed, a large number of potential treatments are in the research pipeline, and investigators believe some of them are likely to be on the market within 10 years.
Scars in the Brain
Near the start of the 20th century in Germany, a homemaker named Auguste Deter showed symptoms of severe dementia at age 51, long before senile dementia commonly occurs. When she died, Alois Alzheimer, a neuropathologist, and his colleague Emil Kraepelin, a psychiatrist, discovered that her brain was riddled with lumpy, oval-shaped clumps outside of neurons—plaques of the protein beta-amyloid—and tangles inside the cells made of a protein that scientists now call tau. In 1906 Alzheimer and Kraepelin agreed to name this combination of memory loss and neuronal scarring Alzheimer’s disease.
This landmark case was a form of the disease that runs in families similar to the one that torments the DeMoes. In such cases, mutations in the genes for any of three different proteins—amyloid precursor protein, presenilin 1 or presenilin 2—spawn abnormal amounts of these proteins. (The DeMoe family harbors a mutation in the presenilin 1 gene on chromosome 14.) How these mutations lead to the buildup of beta-amyloid is not clear. The abundance of the protein is thought to produce plaques, and the plaques spawn tangles, but the pathway is unknown.
The fact that these genetic alterations create both plaques and tangles and inexorably lead to the disease lends credence to the widely accepted hypothesis that these pathological hallmarks cause the dementia, although some uncertainty remains. For example, scientists are confounded by the fact that as many as 40 percent of older people who are autopsied have plaques and tangles in their brains but showed no sign of dementia when they were alive. Thus, some other pathology, still unknown, might be the cause of Alzheimer’s, and the plaques might be either coincidental or a side effect.
Regardless of the causal role of these lesions, their presence after death remains the most definitive diagnosis of the disorder. In the living, doctors typically spot Alzheimer’s from its symptoms along with a physical exam to rule out other causes. Predicting the disease in individuals who have no symptoms has so far been largely limited to people with a family history of the genetic form of the ailment. In these cases, a blood test can reveal whether a patient harbors any of the unfortunate variations of the three culprit genes. If so, he or she will get early-onset Alzheimer’s.
Modern brain scanning has revealed other anomalies—such as shrinkage of certain parts of the brain—associated with the development of Alzheimer’s. But the two most promising methods for diagnosing the disease in the general population, especially in its earliest stages when symptoms are mild or absent, pick up the proteins that lead to the tangles and plaque. Both are now being used in some academic medical clinics and large hospitals.
Pictures of Plaque
One of the most promising experimental techniques for early detection, amyloid imaging, was developed five years ago by psychiatrist William Klunk and radiochemist Chester Mathis of the University of Pittsburgh Medical Center. The technique is relatively noninvasive. A doctor injects a radioactive tracer—a substance called Pittsburgh compound B (PiB)—into a vein in a patient’s arm. The tracer chemically binds to the amyloid, if it is present, in the patient’s brain. Then the person is slid into a positron-emission tomographic (PET) scanner. The tracer bound to the plaques lights up in the scanner image. The result is a picture of the inside of the head that shows how much plaque is present; a little is okay, but too much means trouble. When the process debuted at a meeting of the International Conference on Alzheimer’s Disease in Stockholm in 2004, the audience gasped. The difference between a brain with Alzheimer’s and a normal, healthy brain was obvious: a few scattered plaques dotted the brain of the normal elderly brain, whereas the Alzheimer’s brain was clogged with the lesions.
“When a PET scan is positive, we are very certain there is amyloid in the brain,” says Klunk, who makes a judgment based on the amount of plaque he sees in the brain, although different scientists set the bar at different levels. In March 2007 scientists at Massachusetts General Hospital reported performing an autopsy on a dementia patient who, when he was alive, had undergone amyloid imaging that revealed abundant plaque in his brain. The autopsy uncovered plaques exactly where the images said they were. In a study published in 2008 Klunk, along with Pittsburgh neurologist Milos D. Ikonomovic and their colleagues, replicated the finding, showing the same match in the placement and amount of plaque in an autopsy of another patient who had undergone scanning before he died.
PiB is expensive, costing thousands of dollars for a test, and requires equipment most hospitals do not have, adding to the potential expense. A change in the source of radioactivity would lessen the cost—and new sources, substances with longer half-lives, are in the pipeline, which should allow wider use.
Researchers are also testing a competing technique, involving the use of spinal taps. This method is more invasive, requiring a needle inserted in the lower back to collect cerebrospinal fluid (CSF), the liquid that bathes the brain and spinal cord, which is then analyzed for the quantity of beta-amyloid and tau proteins. The less amyloid in the CSF, the more of it is likely to be in the brain and the greater the likelihood of Alzheimer’s. In contrast, having more tau in the CSF raises a person’s risk. Scientists make the call based on certain threshold levels of these proteins, although the exact concentration cutoffs for diagnosing Alzheimer’s vary among medical centers.
The method holds particular promise for predicting dementia in people with ambiguous signs of cognitive decline. In a study of 750 patients with mild symptoms of dementia published this year, neuroscientist Niklas Mattsson of Sahlgrenska University Hospital in Sweden and his colleagues showed that the technique is sensitive enough to accurately predict, at least 80 percent of the time, which patients would progress to full-blown Alzheimer’s in a year or two. In another study published this year psychiatrist Volker Welge and his colleagues at the University of Duisburg-Essen in Germany examined the CSF of 156 individuals for two forms of beta-amyloid and tau. In 94 percent of the cases, a peek at these proteins enabled the researchers to differentiate Alzheimer’s from other forms of dementia, such as those caused by other disorders, as assessed by symptoms or pathology after death. The test proved superior to the current method of physical exams and medical histories.
Although spinal taps can be painful and risky, research indicates that the CSF test may be more accurate than the tracer technique for predicting Alzheimer’s, says neurologist Randy Bateman of Washington University in St. Louis who is actively studying the technique. The spinal tap technique is also cheaper than a PET scan.
Working out which method is best is one goal of the ongoing Alzheimer’s Disease Neuroimaging Initiative, which began in 2004. The initiative represents the most comprehensive effort to date to determine the best diagnostic techniques and to identify the biological signs of the behavioral changes associated with mild cognitive impairment and Alzheimer’s. At 59 U.S. research centers, doctors examine cognitively impaired patients and healthy volunteers—819 in all—using both the tracer technique and the spinal fluid method.
The results of these studies flow into a central computer at the University of California, Los Angeles, neuroimaging lab, where they are accessible to scientists everywhere on the Internet. The research database is enormous: the U.C.L.A. computer holds more than 32,000 magnetic resonance and PET scans. So far the study has confirmed that the new techniques are indeed better than the present method of diagnosing Alzheimer’s but has not ruled on their efficacy otherwise.
In the future, scientists hope the data will tie changes in a brain image or spinal fluid test with worsening cognition. If the connection is clear, it might be possible to design drugs that target specific pathologies as the disease progresses. (Most drugs now try to aim at the plaques; none seem to work against the tangles.) What is more, if a medication’s efficacy can be assessed early on using a PET scan or spinal tap, then such a technique could cut the cost and length of drug trials dramatically. Doctors might also use such a method to more rapidly assess whether a particular medication is working in an individual patient.
Drugs for Thought
Although there is no cure for Alzheimer’s, a few medications seem to slow its progression in some patients. So-called cholinesterase inhibitors such as Aricept slow the metabolic breakdown of acetylcholine, a chemical involved in nerve cell communication. Alzheimer’s patients typically have low levels of acetylcholine. Slowing the breakdown of the chemical enhances communication between nerve cells and can, in some patients, retard cognitive decline.
Another drug, Namenda, approved for moderate to severe Alzheimer’s, protects healthy nerve cells from the excitatory neurotransmitter glutamate. Damaged neurons, such as those affected by Alzheimer’s, release glutamate in massive quantities that essentially stimulate other cells to death.
Nevertheless, many neurologists say that the current drugs’ effects on a patient’s symptoms are modest at best. “If you put a patient on a drug and took the same patient in a parallel universe without the drug, you might see a difference, but not much,” says Baltimore neurologist Nechama Bernhardt.
Several therapeutic vaccines that target Alzheimer’s plaques and tangles are now in clinical
trials. Unlike traditional vaccines, which prevent disease, these substances are designed to combat it after it appears by stimulating the immune system to destroy the disease-causing proteins. In 2002 Wyeth, working with Elan Pharmaceuticals, had to discontinue testing of a vaccine consisting of beta-amyloid itself, because a few of the subjects developed inflammation in the brain. Nevertheless, the vaccine did slow accretion of the plaques and retard progression of the disease. Wyeth redesigned the vaccine, and testing has resumed.
One controversial drug now in late-stage clinical trials is Dimebon (dimebolin), which improves mitochondrial function and seems to inhibit brain cell death. The drug, an antihistamine, was developed in Russia, and not all Western investigators think that promising preliminary data on the drug meet Western standards. Pfizer and a small San Francisco company, Medivation, are sponsoring the trial. And many more drug candidates are in the offing: the Web site clinicaltrials.gov lists 675 clinical trials of various Alzheimer’s treatments and diagnostic aids.
Although scientists hope that early detection of Alzheimer’s will help them target preventive measures to the right people, no lifestyle remedy has yet been proven to slow the cognitive decline characterizing the ailment. Some widely publicized studies hint at the “use it or lose it” theory, which says that individuals who use their brains—by doing everything from solving crossword puzzles to writing novels—can slow the progression of the disease. In its early stages Alzheimer’s has not prevented creative people from working. Norman Rockwell kept painting, Iris Murdoch kept writing, and Terry Pratchett, the English fantasy writer, is still writing and raising money for Alzheimer’s research. But the idea that engaging in intellectual tasks can significantly forestall dementia remains undocumented.
Linking Hearts and Minds
Nevertheless, maintaining cardiovascular health—and therefore good blood flow to the brain—may improve the function of the healthy neurons that remain. Both cardiovascular disease and Alzheimer’s also share risk factors, including high cholesterol. Thus, being physically fit might be beneficial generally for maintaining a sound mind. “If you can maintain heart health, it’s going to help,” Klunk says. “It won’t stop the amyloid, but you might live with it for a longer time.” [See “Fit Body, Fit Mind?” by Christopher Hertzog, Arthur F. Kramer, Robert S. Wilson and Ulman Lindenberger; Scientific American Mind, July/August 2009.]
A 2005 population study by researchers in Finland and Sweden called out obesity in mid-life, high blood pressure and high cholesterol as key risk factors for developing dementia within two decades—another piece of data suggesting that heart health and brain health are linked. In addition, at least one genetic quirk connects brain health to heart health: people who have a variant called ApoE4 of the gene for apolipoprotein E, a protein involved in lipid metabolism, appear to be more susceptible to both atherosclerosis and Alzheimer’s.
Cardiovascular conditioning might help on another front if, as some believe, Alzheimer’s is linked to diabetes. In diabetes, the body fails to make, or becomes resistant to, the hormone insulin, which converts sugars, starches and other food into energy. Neurobiologist William L. Klein and his colleagues at Northwestern University showed in 2008 that beta-amyloid severely disrupts insulin signaling, which is important for memory functioning, in neuronal cell cultures, suggesting that a brain-specific form of diabetes may play a role in Alzheimer’s. Consistent with this idea, those with diabetes stand a higher than average chance of the disease developing. Thus, habits such as exercise and healthy eating that can cut a person’s risk of diabetes may also lower his or her chances of developing Alzheimer’s.
For the DeMoes, proven preventive measures cannot come too soon. Rose’s aunt, Lori McIntyre, 49, is already experiencing worrisome difficulties. “It is frustrating,” McIntyre says. “One day you know something, the next day, poof, you just don’t. Sometimes it just gets to you.” As with many Alzheimer’s patients, she is taking medication for depression. There are personality changes, she adds: “You lose interest in certain things like golfing or doing fancy work. You aren’t as good at things as you used to be and tend to steer away from them. You repeat things a lot. There is confusion. It takes twice as long to get the day in order.”
The unlucky ones in the family who test positive before their memory wanes just wait and worry. Did I forget my keys because of normal aging, or is my lapse the first sign of the slide into what Ronald Reagan, himself a victim, described as the “sunset?” Why did her name slip my mind? Why did I miss that turnoff? Rose, who recently married, knew that if she tested positive she would not allow herself to become a mother. “I wanted a normal life,” she says. And amid this uncertainty, she gave birth to a child, now a toddler, named Briana.
Note: This story was originally printed with the title "Decoding Dementia"