The end for the Alzheimer's patient is a horror: The person is mute,bedridden, adrift from the thoughts and feelings that make up a life. Thebrain undergoes an equally disturbing transformation, shrunken by as much ashalf, mottled all over with hardened plaques. Where neurons used to cracklewith messages, all that's left are twisted threads, fittingly referred to byscientists as tombstones.
Now, after years of work detailing this devastating finale, scientists areincreasingly tracking the path of Alzheimer's back to its roots.
They're scrutinizing how certain proteins gum up the brain mechanismsneeded for memory. They're developing blood tests and other ways to diagnoseAlzheimer's early. Researchers are even testing whether drugs such aspainkillers and estrogen can prevent the disease.
For a society facing an epidemic of Alzheimer's - an estimated 360,000 newcases each year - getting at these early stages is critical. But it's alsosignificant because years and possibly even decades before symptoms surface,subtle changes are already under way in the brain.
"It's like an iceberg building," said Dr. Dennis Selkoe, a professor ofneurologic diseases at Harvard Medical School. "It takes a while until itbreaks the water."
Doctors want to find a way to intervene. But Alzheimer's raises some of themost daunting questions in medicine, because the condition takes over thehuman body's most complex organ, one that is still largely a mystery: thebrain.
Thirty years ago, physicians thought Alzheimer's was an inevitableconsequence of aging. But they came to see that only certain people sufferedfrom what was, in fact, a disease. Its hallmarks are sticky protein deposits,or plaques, and abnormal tangles in nerve cells.
By killing brain cells, Alzheimer's causes patients - who have includedRonald Reagan, Iris Murdoch, E.B. White, Rita Hayworth and Willem de Kooning -to deteriorate to an infant-like state. Their thinking and memory erode, theirpersonality changes, and they eventually forget to feed or bathe themselves.
"We can tell you in horrifying detail all the later stages of the disease,"said Dr. Marcelle Morrison-Bogorad, associate director of neuroscience andneuropsychology at the National Institute on Aging. "Now, we're beginning toget a handle on the earliest stages."
This month, Selkoe's study of rats in the journal Nature showed which formof the protein involved in Alzheimer's - beta amyloid - builds up in thebrain. The work proved that the protein does its damage by interfering withmemory circuits.
Many scientists are trying to figure out ways to pick up these and otherbrain changes. Researchers have already identified several genes that cancause Alzheimer's. They've also discovered that some neuropsychological testscan reveal deficits, such as visual memory errors, that are prevalent inpeople who go on to develop the disease.
Some physicians are enhancing imaging techniques so they can see themicroscopic deposits and tangles in the brains of living patients. Right now,there is no way to view this destruction until autopsy.
"Somehow, you have to look in there and see if the treatments are working,"said Dr. William Klunk, an associate professor of psychiatry at the Universityof Pittsburgh School of Medicine. He and Dr. Chester Mathis are testing a dyethat can penetrate the blood-brain barrier and highlight the plaques during aPET scan.
In another approach, a recent study suggests a blood test might be able todetect Alzheimer's pathology in the brain, even before a person showssymptoms.
Dr. David Holtzman, an associate professor of neurology at WashingtonUniversity School of Medicine, along with Dr. Steven Paul at thepharmaceutical company Eli Lilly, reported that intravenously injecting micewith an antibody to the beta amyloid protein decreases the level of theharmful protein. Apparently, the antibody flushes it from the brain to thebloodstream. There, the amyloid doesn't appear to cause any problems - and canbe measured.
Other scientists are working their way back even earlier in the progressionof Alzheimer's, by trying to prevent it.
About 5 percent to 10 percent of people who develop the condition have theinherited, or familial, form, which means they'll get Alzheimer's early,between the ages of 40 and 60.
But the bulk of patients with the disease develop it after age 65. One in10 adults over 65, and nearly half of those over age 85, have Alzheimer's.These people's risk is probably influenced by factors that can be changed,such as environment or diet.
Some findings in mice offer hope that even simple steps, such aslow-calorie diets or taking folic acid, might help nerve cells endure agingand resist the disease, according to Dr. Mark P. Mattson, chief of theneurosciences lab at the National Institute on Aging's Gerontology ResearchCenter.
Nationwide, seven large-scale clinical trials are looking at ways toprevent or delay the disease in healthy people. Physicians are testing agentssuch as estrogen, anti-inflammatory drugs and gingko.
One of the more intriguing avenues scientists are exploring is the complexrelationship between Alzheimer's and heart disease. According to severalstudies, lowered blood pressure in mid-life seems to correlate with a reducedrisk of Alzheimer's later. At the same time, other research has shown that themost common type of cholesterol-lowering drugs, statins, might also decreaseone's risk of Alzheimer's.
The findings hold out promise that treatments proved safe and effective forone major disease could be tapped for another. But experts aren't expectingeasy answers.
"We can describe things, but we can't say how they work. Quite often, ourattempts to explain how they work is just sort of skating over the surface ofour ignorance - not because we're stupid, but because there's so much toknow," said Morrison-Bogorad of the National Institute on Aging. "There arehuge questions."
Scientists need to figure out why Alzheimer's starts, where it starts, howit progresses and what can stop it. They have to decipher why some neurons arevulnerable to the disease, and conversely, what protective factors enableother nerve cells to survive.
But the brain is a tough region to access for study. And with a diseasethat lasts years and years, testing treatments takes a long time. Makingmatters harder, no animal gets Alzheimer's, and scientists had to create anexperimental model - a genetically modified mouse.
Researchers were reminded of these difficulties recently when a promisingclinical trial in Alzheimer's patients had to be halted. The therapy, avaccine, had reversed the formation of plaques in mice. But in the humantrial, a small percentage of participants suffered a serious side effect,brain inflammation.
In the meantime, to help the rest of us ward off Alzheimer's, a stream ofstudies suggest all sorts of steps, from doing crossword puzzles to takingvitamins and even engaging in leisure activities such as watching movies.
But the truth is, no one knows what can be done to stop this slow killer.At least not yet.