Ghetti, professor of neuropathology at the Indiana University School of Medicine in Indianapolis, receives about fifty brains per year from across the United States. The brains are brown on the outside, partially a result of the formalin in which they are preserved, but not what one would expect after constantly hearing them referred to as "gray matter." Inside, they are off- white, the color of three-day-old snow on the side of a road.
Under the microscope, a brain slice looks like a strange landscape seen from the space shuttle, with tiny black specks that could be ponds and larger red splotches--forests, maybe--and an occasional river sweeping across the terrain. There's a wondrous flow to the whole that is quite beautiful. Beautiful, that is, in the way a mushroom cloud is beautiful, if its form is detached from the horrifying reality of what is actually happening. For the brains Ghetti analyzes belonged to people who were afflicted with dementia when they died. Dementia is a gradual deterioration in mental functioning marked by memory loss as well as impairment in at least one other area of cognition.
In the later stages of Alzheimer's disease, which occur years after the onset of initial symptoms, patients experience profound memory loss (short and long term) along with widespread disability. They may become disoriented and severely depressed, lose control over bodily functions, and fail to recognize loved ones or even remember who they themselves are.
As the wife of an Alzheimer's disease victim once told a Congressional committee, the experience is like "a funeral that never ends." The memories, the minds, the very identities of patients slowly pass away while the body lives on.
These symptoms are linked to several characteristic brain abnormalities-- the kind that Ghetti sees when he examines brains after death. Among them are (a) loss of neurons, or brain cells; (b) plaques, or deposits of a substance called beta-amyloid, between neurons; and (c) tangles inside neurons composed of a protein called tau.
At present, Alzheimer's dementia afflicts between 3 and 4 million Americans, most of them over the age of sixty-five. In fact, the older a person gets, the greater his or her chances of getting the disease. At sixty-five, the odds of having Alzheimer's disease are less than one in fifty. By eighty-five, those odds have risen to as high as one in two. Since the number of Americans over eighty-five is projected to double or even triple over the next thirty years, the prevalence of Alzheimer's disease will increase dramatically, placing tremendous burdens on families and the U.S. health care system.
Unfortunately, the cause of Alzheimer's disease is unknown. The disease is difficult to diagnose, particularly in its early stages. And there is no known cure.
One of Ghetti's key associates is Martin Farlow, associate professor of neurology, who directs the Center's outpatient clinics. Ghetti and Farlow have collaborated on studies of hereditary forms of Alzheimer's syndrome and with other dementias, including Gerstmann-Straussler-Scheinker disease. Farlow has also investigated various drugs that may prove useful in treating senile dementia. Dr. Merrill Benson (Medicine), Dr. Michael Conneally (Medical and Molecular Genetics), Dr. Steven Dlouhy (Medical and Molecular Genetics), Dr. Hugh Hendrie (Psychiatry), and Dr. Debomoy Lahiri (Psychiatry) are among the many other IU faculty involved in the Alzheimer's research.
A different grant by the National Institute on Aging is supporting the research of yet another faculty member, Joe Christian, chair of the Department of Medical and Molecular Genetics. Christian is collaborating with scientists from several other universities on a study of aging twins to try and understand the roles that heredity and the environment play in the development of Alzheimer's disease.
Now Alzheimer's disease may be joining that list. Over the years, scientists have identified several dozen families around the world in which a form of Alzheimer's disease characterized by early onset (in one's forties) passes from generation to generation. As it happens, one of these families lives in Indiana. Three years ago, Benson, Farlow, Ghetti, and their colleagues discovered that Alzheimer's disease in this family was associated with a mutation on a particular gene, the amyloid precursor protein (APP) gene, located on chromosome 21 (the one involved in Down's syndrome).
To be sure, finding an association between two phenomena does not prove that one causes the other. But Farlow is confident that there is a cause/effect relationship. "In this family the evidence would clearly indicate that this mutation, this change in the gene, somehow is causing the disease to occur," he says. He is not sure exactly how it happens, but apparently the mutation disrupts the process by which the large amyloid precursor protein breaks down into the smaller beta-amyloid protein, leaving behind an insoluble form of beta-amyloid that accumulates in plaques in the brain.
This connection between the APP gene mutation and familial Alzheimer's disease was only the second ever to be reported in the world's scientific literature. Over the past three years, similar mutations have been found in a few other families with early-onset forms of Alzheimer's disease. Ghetti, Farlow, Dlouhy, and Karen Hsiao, a colleague from the University of California, San Francisco, have also discovered a mutation on a different gene that causes a rare form of dementia called Gerstmann-Straussler-Scheinker disease (see sidebar The Frontier of Pathology).
Although no such gene mutations have been found in the most common form of dementia--nonfamilial, late-onset cases of Alzheimer's disease--available evidence suggests that genetic predisposition may be the cause here as well. Studies have shown, for example, that parents, siblings, and children of people with Alzheimer's have a 50 percent chance of developing the disease if they live to their late eighties--"just what you would expect if a single gene were the cause," says Christian. Still, this evidence is far from conclusive. "Neither the linkage studies in familial Alzheimer's disease nor the family history investigations of other cases can answer many questions about the roles of genes and the environment or their interaction," Christian and his colleagues write.
There may be a way to answer some of those questions, suggests Christian: twin studies. The method is relatively simple, in theory at least. Compare identical twins (those who came from the same egg and therefore have the same genetic material) with fraternal twins (those who came from two different eggs).
If Alzheimer's disease is genetic in origin, and if one identical twin has it, the other should eventually get it as well. In other words there should be 100 percent concordance among identical twins, compared with 50 percent for fraternal twins. Also, if one identical twin gets Alzheimer's disease at, say, age seventy-eight and the other doesn't get it until age eighty-six, then researchers may be able to identify environmental factors that can delay the onset of the disease.
Unfortunately, because of logistical problems, most twin studies to date have been small and inconclusive. In a major advance over these studies, a group of researchers at Duke University is investigating Alzheimer's disease in a very large group of twins: the National Academy of Sciences registry of aging twin veterans. The registry comprises about 8,000 pairs of male twins born between 1917 and 1927 who have served in the U.S. military. It is a veritable gold mine, not just for studies of dementia but for other diseases and characteristics of aging as well. Christian serves on the National Academy of Sciences study committee that oversees the twin registry and is a consultant to the Duke investigators.
Out of this mine, forty Alzheimer patients have been identified with an identical twin and sixteen with a fraternal twin. Preliminary studies indicate that the current concordance rate for the identical twins is 35 percent. None of the fraternal twin pairs is yet concordant. Of course, the subjects are still relatively young for an Alzheimer's study--sixty-seven to seventy-seven years old. As they move into their eighties and nineties, the study should contribute to an improved understanding of genetic and environmental factors in nonfamilial Alzheimer's disease.
Following up on leads from previous studies, Farlow and Ghetti took samples of cerebrospinal fluid from the Indiana early-onset family members who were known to have the disease or to be carrying the gene."What we found," Farlow explains, "was that in affected patients in this family, the level of the soluble form of the amyloid precursor protein was low, and in patients who were gene carriers, the level seemed to be intermediately low, a little bit decreased from normal but not as low as the patient who was already affected."
What this all suggests is the exciting possibility that levels of the amyloid precursor protein in cerebrospinal fluid may prove to be a marker for Alzheimer's disease, assisting diagnosis.
One such drug is called Tacrine. "Tacrine functions by inhibiting an enzyme that breaks down acetyl-choline," explained Farlow. "And if you inhibit its breakdown, what little is there in the brain will stay around longer, so effectively you'll get higher levels." The results of a series of studies have been promising. "It has been found," he says, "that Tacrine does improve memory and cognition in some patients with Alzheimer's disease--not all patients but in some patients. The effect appears to be mild, but it is definite." At present, Tacrine is the only drug that has been approved for physicians to prescribe for senile dementia.
Or drugs may be developed that will delay onset. "If you can raise that age of onset enough," Farlow says, "then you can tremendously mitigate the effects of this illness on the population. Finally, we will continue to search for better drugs to treat Alzheimer's when it does strike."
Even if Alzheimer's is brought under control, the battle against other forms of dementia will no doubt continue. To wit, Ghetti got a brain in the mail recently--this one from Texas--which, as far as he could tell, did not fit any known classification of dementia. "It's a new disease," he says. There is no telling what gene or protein or as-yet-undiscovered agent is responsible or what suffering it may cause. But with Ghetti, Farlow, Christian, and their colleagues from the Indiana University School of Medicine on its trail, you can bet the disease will yield its secrets before long.