GIFT OF LOVE

By J. MADELEINE NASH/MANKATO

Even as she sped past her 100th year, Sister Mary projected the energy and enthusiasm of a much younger woman. With the aid of a magnifying glass, she kept abreast of national affairs by reading newspapers and magazines. With the aid of a globe, she prayed for the women and children of the world, one continent at a time. In fact, so savvy did Sister Mary seem, so tuned in to her surroundings, that University of Kentucky epidemiologist David Snowdon began to think of her as a kind of gold standard for successful aging.

But when Sister Mary died--in 1995, three months short of her 102nd birthday--an autopsy of her brain revealed a startling secret. Everywhere Snowdon and his colleagues looked, they saw signs of devastation, from microscopic plaques and tangles to gaping holes where millions of brain cells had died. Sister Mary, they realized, had been living with an advanced case of Alzheimer's disease--so advanced, says Snowdon, that it was hard to understand how she could have conducted herself with such clarity and coherence.

Gradually Snowdon and his colleagues began to understand that Sister Mary was not unique. Out of a group of 61 deceased nuns whose brains showed clear signs of Alzheimer's disease, a large fraction, 19 in all, seemed to have escaped the confusion and memory loss that make this form of dementia so devastating. The reason? As Snowdon and his team reported in the Journal of the American Medical Association last week, these nuns, unlike their counter-parts whose symptoms were severe, had not suffered from strokes--particularly the small strokes so commonplace in the elderly. Only 57% of the stroke-free nuns developed dementia, compared with 93% of nuns with a history of ministrokes.

Other Alzheimer's experts were quick to herald the finding as both provocative and extraordinarily hopeful, for it provides what may be the clearest sign yet that a medically treatable condition can accelerate the decline of Alzheimer's patients and make the difference between independent living and a nursing home. "By preventing strokes," says University of Hawaii neurologist Dr. G. Webster Ross, "we may actually be able to postpone the development of symptoms in people who have Alzheimer's."

The link to strokes was the highlight of a flood of Alzheimer's news last week--including encouraging reports on drugs that alleviate the symptoms of the disease and perhaps even reduce the risk of developing it. Short of a cure, says Zaven Khachaturian, director of the Alzheimer's Association's Ronald and Nancy Reagan Research Institute, more welcome news cannot be imagined.

Even if medical researchers succeed in only reducing the symptoms of Alzheimer's, they will have accomplished a great deal. About 4 million Americans suffer from the degenerative brain disorder, and caring for them costs some $100 billion a year. Before the middle of the next century, the aging of the baby-boom generation is expected to swell the number of Alzheimer's sufferers nearly threefold. Measures that delay the onset of symptoms in these patients by just five years could cut the associated health-care costs as much as 50%.

The link between stroke and dementia is not new, but seldom has it been called out so clearly. One reason is that Snowdon and his team had access to a sizable control group and thus were able to compare brain tissue of normal people with that of diseased individuals. In 41 nuns who did not have Alzheimer's-like brains, researchers found, strokes caused no measurable decrease in overall mental competence. But in nuns with Alzheimer's, just one or two strokes--small strokes that left swirls of dead tissue no bigger than a pencil tip--were enough to trigger a precipitous decline. "One brain disease is bad enough," Snowdon observes. "But when you add a second disease to it, you're in real trouble."

Like many medical researchers, Snowdon has cultivated an affectionate, intensely personal relationship with his subjects, all members of a Roman Catholic religious order, the School Sisters of Notre Dame. Before his group publishes a new paper, Snowdon carefully makes the rounds of all the convents to make sure the sisters hear the news first. About a month ago, for example, he stopped by the rambling brick convent in Mankato, Minnesota, which serves as the headquarters for one of the order's seven U.S. provinces. "You've got to be good friends before you ask somebody for their brain," he jokes as he arrives, giving an elderly nun a big grin and a hug. At certain times, Snowdon says, he feels as if he never left parochial school. One such moment occurred when a nun recently suggested that he ought to think about trimming his shoulder-length hair.

Snowdon launched the Nun Study in 1986 as a way to take a broad look at the physical and psychological aspects of aging. But in 1990 he decided to narrow the focus to Alzheimer's. That's when he approached the order's U.S. leaders with a sensitive question. Would the nuns be willing to do more than take psychological tests and give blood samples? he wondered. Would they be willing to donate their brains? Like a politician campaigning for votes, Snowdon traveled from one convent to the next, making his pitch. In Baltimore, Maryland, he remembers, Sister Mary was the first to endorse the project. "Sign me up!" she said. In the end, 678 nuns who were 75 or older enlisted. To them, participating in the study seemed an extension of their mission to care for the sick and the poor. "A person with Alzheimer's disease," said an elderly sister, "is one of the poorest people I know."

Every few weeks or so, one of the nuns in the study dies, and her gift to science--a beautifully sculpted, convoluted mass of tissue that once embodied a devout mind--arrives at the University of Kentucky, where it is processed, assigned a number and then locked away like a rare book. Each brain is photographed, weighed and sliced into sections. From these sections researchers remove the barest slivers of tissue, which they examine under high-power microscopes. What they are looking for is the freckling of brownish plaques and blackish tangles that are the telltale marks of Alzheimer's. While such blemishes may show up in virtually any area of the brain, they are usually densest in the hippocampus, the seahorse-shaped region that is critical to memory.

In addition to their brains, the nuns have provided Snowdon with a wealth of biochemical and behavioral information-- blood samples, test scores and even autobiographical sketches written in their teens and 20s. Last year, Snowdon and his colleagues caused a stir when they found a tantalizing if tenuous connection between the nuns' schoolgirl writing styles and the likelihood of developing Alzheimer's later on. Out of a group of 25 nuns who died between 1991 and 1995, the researchers reported, those whose writing samples contained the lowest density of ideas per paragraph were the most likely to develop Alzheimer's. Could it be, Snowdon wondered, that Alzheimer's starts so early?

To answer that question, scientists must first understand what causes Alzheimer's, and right now they have only intriguing clues. The most popular hypothesis holds that the disease process starts when a protein called beta amyloid accumulates outside nerve cells, forming the deposits known as plaques. Among other things, plaques appear to impair the ability of neurons to absorb glucose from the bloodstream, generating an energy crisis inside the cell. A competing hypothesis maintains that Alzheimer's begins not with beta amyloid but with a protein called tau. Abnormal variants of this protein, say scientists, clutter the interiors of neurons with tangled filaments that disrupt cellular metabolism.

Which are more important, the plaques or the tangles? As researchers begin to identify the genes that contribute to formation of these lesions, they are finding evidence that supports both camps. Families that carry a defective version of a gene involved in making beta amyloid, it is well established, have high rates of Alzheimer's, which lends weight to the beta amyloid theory. But many more people, observes Duke University neurologist Dr. Allen Roses, carry an Alzheimer's-susceptibility gene known as Apo-E4, which produces a protein that appears to affect tau. Individuals who carry two copies of this gene, Roses has shown, have an elevated risk of developing Alzheimer's before age 70. And if they suffer a stroke, warns another report published in last week's J.A.M.A., they are more likely to develop full-blown dementia.

By calling attention to the unhealthy synergy between Alzheimer's and stroke, the School Sisters of Notre Dame have performed an enormous service. But they're not yet finished with their work. Long-term epidemiological studies, like fine wines, improve with age, and thus new findings from the Nun Study can be expected to enrich medical knowledge for many years to come. Indeed, long after he and his colleagues retire, Snowdon imagines, nuns like Sister Mary will continue to enlighten Alzheimer's researchers. This, of course, is the point. "These women were teachers all their lives," says Snowdon, "and now they've found a way to continue teaching after their deaths."