Vanishing Minds
New research is helping Alzheimer's patients cope--and hope
Imagine: Inside your head, your memory is a dark, vast lake, and the waters are receding. Ripples that used to lap steadily on shore, bringing with them the time of day, the names of coworkers, and the location of your car keys, now barely reach. As the waters retreat farther, they take with them your ability to count, to drive, and to recognize the face of your wife or husband. Soon the lake is but a distant, dim shadow, holding words you can no longer speak and bodily functions you can no longer control. You are kept from it--from what used to be you--by an impossibly wide stretch of exposed and featureless sand.
For people with Alzheimer's disease and their families, this shrinking lake is not just a metaphor but a painful reality. "Time is what this is all about," says Pierre Tariot, an Alzheimer's specialist at the University of Rochester Medical Center in New York and now a caregiver as well. "If my father-in-law knows how to flush the toilet and where to poop for another nine months, that's huge for our family."
Buying time. Tariot and other researchers are combining new and existing therapies to buy as much time as possible, staving off brain failure for months and sometimes years. Last week, at the International Conference on Alzheimer's Disease and Related Disorders in Philadelphia, scientists showed for the first time that a drug could slow the deterioration from mild cognitive impairment to full-fledged Alzheimer's. Other drugs can reduce the agitation and irritability that comes with the disease, keeping patients out of institutions. This reflects a growing awareness that Alzheimer's is more than memory loss; it is a syndrome of psychiatric disorders as well. New brain scans are making earlier, clearer diagnoses possible, and very early experiments point to drugs that may limit Alzheimer's-related brain damage. A novel regimen of task-training, reported just last month, showed that people with mild Alzheimer's could still learn new skills (box, Page 76). "We have to attack Alzheimer's in multiple ways," says Steven DeKosky, director of the Alzheimer's Disease Research Center at the University of Pittsburgh. "We have no trouble doing this with cancer. But now we're learning to apply this many-pronged approach to Alzheimer's, too."
Along with the hope, there's stark reality. Drug benefits are still modest. And there's been gloomy news on the prevention front: Vitamin E and the heart drugs called statins, which had shown some promise in reducing the risk of Alzheimer's, have flunked their most recent tests. And hardly anyone at the Philadelphia meeting was talking about magic stem cells: Though they received a burst of publicity in the wake of President Reagan's death from complications of Alzheimer's, the cells seem more appropriate for treating other brain disorders.
All this is playing out against a drumbeat of increasing urgency, as the disease makes inroads against an aging society. The rate of Medicare beneficiaries with Alzheimer's more than tripled during the 1990s, and the number of sufferers is projected to balloon from the current 4.5 million to 16 million by 2050. "Remember, for baby boomers in this century the average age of death is 85," warns Tariot. "At 85, the chance of Alzheimer's is almost 50 percent. So look to your right and look to your left. One of those two people will probably get it."
Getting it later, not sooner, would be an improvement, of course. For many people, a condition called mild cognitive impairment, or MCI--you forget things regularly, but your judgment and reasoning are intact--is a precursor to Alzheimer's. So Ronald Petersen of the Mayo Clinic took about 750 people with MCI and put some of them on Aricept, a common Alzheimer's drug, and some on a placebo. At first, he reported in Philadelphia, fewer people in the Aricept group developed Alzheimer's. Unfortunately, the rates evened out at the end of an 18-month period, so Petersen described the study as encouraging but no more than "a foot in the door."
Disappointment. It was also a small boost for Aricept, which works by limiting the destruction of a neurotransmitter, acetylcholine, in the brain. It's the most frequently prescribed Alzheimer drug, but a recent study in the medical journal Lancet questioned its value. After following over 500 Alzheimer's patients for three years, the study reported those on Aricept ended up disabled or in nursing homes just as often as did those on a placebo. The research has generated a strong reaction. Sam Gandy, an Alzheimer's researcher at Thomas Jefferson University in Philadelphia, points out that the study showed Aricept did have some early benefits, delaying cognitive decline. Others are even more optimistic. Says Rachelle Doody, director of the Alzheimer's Disease Center at Baylor College of Medicine in Houston: "Other studies show the disease can be stabilized, often for years, with treatment. I can't emphasize that enough."
For more severe cases, the newest kid on the block is memantine, sold as Namenda and approved last fall by the Food and Drug Administration. In tests in people in later stages of Alzheimer's--when patients lose the ability to dress or clean themselves--the drug slowed their decline by 50 percent. Again, this benefit generally lasted for no more than a year. Memantine works on a different principle than Aricept, inhibiting a chemical that overexcites brain cells, leading to cell damage and death. Because of that, says Barry Reisberg, a psychiatrist and Alzheimer's specialist at New York University, it lends itself to combination therapy: "It's likely that doctors will be giving cocktails of Aricept and memantine to their patients." Indeed, a study that paired the drugs showed that not only did patients' cognition stabilize for six months, but their temperament--their levels of crankiness--improved as well.
Patient agitation and irritation are a huge and neglected aspect of Alzheimer's. "The public thinks Alzheimer's is a memory disease. But, in fact, there are lots of neuropsychiatric symptoms," says Constantine Lyketsos, a psychiatrist at the Johns Hopkins University School of Medicine. "Apathy, depression, agitation are the most common problems." Adds Reisberg: "Alzheimer's patients often develop delusions. They think their family is stealing things from them, for example. And they get very aggressive and irritable towards their spouse." That kind of behavior, studies have shown, hastens patients down the road toward institutionalization, since families can't cope with it.
The agitation often starts as patients get frustrated with themselves, as simple memories start slipping away, says Janelle Lafser. Her husband, Frank, was diagnosed with Alzheimer's in 2002, at the unfortunate early age of 53, but began having problems several years before that. "We'd have a date to meet someone, and he'd come up and ask me what time we were leaving the house. I'd tell him. And then 20 minutes later he'd come up and ask me again," says Janelle, of La Quinta, Calif. "I'd tell him, and then 10 minutes later it would happen again. And again. I'd get irritated, and he'd get agitated." Frank started having trouble doing the household bills, got seriously depressed, and told Janelle, "I just can't do it anymore." A former executive at Sherwin-Williams, he declined to the point where he couldn't hold a job mixing paint at a local hardware store.
Calming effect. Fortunately, there have been some real advances in the treatment of agitation, depression, and other symptoms in people with dementia. Doctors have tried using traditional antipsychotics, but they have unpleasant side effects like heightened cholesterol levels and movement difficulties akin to Parkinson's disease. Worse, recent studies have indicated a higher risk of stroke. In Philadelphia, Tariot presented the results of a trial of a newer drug, quetiapine, sold as Seroquel. In a 10-week study of about 300 patients in nursing homes, the medication reduced agitation and aggression by about 20 percent, but with few of the side effects seen in other drugs. The medication also alleviated depression. The National Institutes of Health is currently sponsoring a longer trial of the drug, along with another medication called risperidone and several other antipsychotics. The results should be available next year.
But drugs are only useful with an accurate diagnosis. For the Lafsers, that diagnosis came courtesy of a PET scan of Frank's brain. Because he started showing problems at such an early age, doctors didn't think Frank had Alzheimer's. They diagnosed serious depression, but antidepressants were no help. His performance on cognitive tests--remembering shapes, repeating lists of words--didn't fit the standard Alzheimer's profile. Finally, Janelle insisted on a PET scan, and it showed reduced activity in brain regions typical of Alzheimer's. "It's devastating to hear that, but it also felt like a ton of bricks being lifted off my shoulders," says Frank. Janelle noticed the difference immediately. "He stopped blaming himself. And I stopped being angry with him, because I realized it's not his fault."
"PET is a direct way to look inside a person's skull to see activity, more direct than a battery of psychological tests," says Daniel Silverman, a brain-imaging specialist at the University of California-Los Angeles. The scan measures the energy used by brain cells; damaged cells, in an Alzheimer's patient, use less energy, and the loss usually shows up in particular brain regions. Standard neurological workups are highly accurate--on the order of 90 percent--but when PET scans are added to standard tests, the rate of missed Alzheimer's diagnoses falls from about 8 percent to about 3 percent. PET scans also help doctors distinguish Alzheimer's from other types of dementia, another study has shown. Such results recently prompted the federal government to announce its intention to expand Medicare coverage to PET scans for Alzheimer's testing.
A step backward. The news about preventing Alzheimer's, however, is not as good. Statins, the cholesterol-lowering drugs, had been linked to a lower incidence of Alzheimer's in several small studies. Researchers speculated that the drugs prevented some inflammation in the brain that led to cell damage. But in Philadelphia, data from three trials that followed about 8,300 people for several years showed no protective effect. Says Doody: "I see patients who come in who have statin prescriptions purely for their Alzheimer's. We have no evidence to support this. Nor evidence supporting antioxidants." Petersen's study of MCI patients also looked at the effects of the antioxidant vitamin E and found no benefit.
So most of the new hopes center on new approaches to therapy. One drug, called Alzhemed, appears to reduce levels of the protein beta-amyloid, which forms the plaques seen in dying regions of the brain. But no one has yet shown the drug eliminates the plaques, or if it slows or prevents actual memory problems. Another compound, an antibody to beta-amyloid, does appear to reduce plaques--but only in three patients so far. And again, this may not affect the course of the disease. Researchers think it will be at least six or seven years before they have better answers. "These are promising avenues," says Reisberg. "But we just don't know where they are going to take us."
This story appears in the August 2, 2004 print edition of U.S. News & World Report.