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In November 1994, Ronald Reagan announced that he was suffering from Alzheimer disease (in using eponyms to designated diseases, the powers that be recommend avoiding the possessive). It was the last public statement he was to make. Since then, those around him have been chary of saying much, but it appears that the former President has declined precipitously. Reagan no longer greets admirers with his trademark, slightly startled way. He cannot carry on a conversation and he recognizes only a handful of people. His memory is now severely impaired. Nancy Reagan does not permit journalists or, for that matter, any but a few close friends to visit him. The gipper is housebound in their BelAir mansion, and his beloved ranch in the Santa Ynez Mountains was sold years ago. Unfortunately, things will get even worse.

Alzheimer disease begins with an insidious loss of memory and other cognitive skills and ends with the patient bedridden, incontinent, unable to speak, barely aware of family and friends, and totally dependent in all aspects of daily life. The decline is slow but inexorable, and extremely painful to loved ones. The only possible blessing is that before the end, the individual loses awareness of the depths of his or her illness.

My first clinical contact with a person with advanced Alzheimer disease occurred when I was a medical student. I was assisting an intern in the workup of a man with a high fever. As we prepared to do a spinal tap (a standard part of the workup of dementia of unknown cause), the intern repeatedly told the man not to move. The patient repeatedly said, "O.K." Just after the young doctor had successfully inserted the 4-inch needle into the spinal canal, the patient stood up and ran out of the room, naked, the needle bobbing in his back. We gave chase and, with the help of two nurses, physically restrained him for his own safety. He was not being ob streperous; he simply could not remember even for seconds the simple instructions that he had been given.

Ronald Reagan is the most famous of the approximately eight million Americans who suffer with Alzheimer disease. Less well known is the fact that his brother, Neil, had advanced Alzheimer disease when he died in December of 1996, and (although awareness of the disorder was much lower back then so we cannot be sure of the diagnosis) that his mother, Nellie, probably also was affected. The Reagan family's troubles emphasize an important point. This most common disorder of old age is often familial and arises in many cases due to a genetically determined predisposition.


The first person to be diagnosed with Alzheimer disease was a middle-aged German woman who had begun to suffer severe memory loss at the age of 51. She was followed for several years by Dr. Alois Alzheimer, a 43-year-old research neurologist and psychiatrist then working in Munich. When the woman died in 1906, Alzheimer obtained permission from her family to perform an autopsy and to study her brain tissue. A year later he published a short paper describing the severe dementia from which she had suffered (before death she had lost her ability to speak) and hypothesized that her illness was caused by the presence of unusual-looking material that he had seen scattered through her brain cells. Alzheimer was an astute observer. The original case report includes a clear description of the plaques and fibrillary tangles that are today still the microscopic hallmark of the disorder. Because there are no biochemical markers for the disease and because dementia has many causes, an unequivocal diagnosis still can only be made by autopsy.

In 1907 the pathological findings in senile dementia, the dementia seen in otherwise healthy old and very old people, had already been characterized. Physicians thought that most cases arose due to vascular disease (hardening of the arteries). They also were aware that dementia occasionally arose for no discernible reason in much younger adults in their 40s and 50s, but until the research by Alzheimer, no one had formally studied their brain tissue after death.

Alzheimer's work led Emil Kraepelin, at the time the world's leading proponent of a biological view of psychiatry (he was one of first physicians to study schizophrenia), and one of Alzheimer's mentors, to conclude in 1910 that his student had described a unique "presenile" form of dementia. It was Kraepelin who suggested that this clinical entity should be named in honor of his student, a recommendation powerful enough to ensure that the honor was bestowed. Unfortunately, Dr. Alzheimer developed rheumatic heart disease, and died in 1915 at the age of 51, just as World War I was curtailing most medical research. After the war no one took up the work that he had begun, and two generations slipped away before the disease he characterized again received serious scientific attention. Writing about Alzheimer disease in 1948, R.D. Newton, a British neurologist who was instrumental in stimulating renewed interest in presenile dementia, lamented that in four decades there has been "little advance towards a solution of the problem."

The hiatus is understandable. During the period from 1910 to 1950, physicians faced many other more urgent clinical problems. In the early years of this century, the median life expectancy in the United States and western Europe was still less than 50. Tuberculosis (known as the white plague) was the number one cause of death, childhood mortality was immense, and childbirth was a life-threatening experience. Streptococcal pneumonia killed hundreds of thousands of people each year. The diseases and disabilities of the elderly had a low priority in American and European medicine. Geriatrics was not yet dreamed of as a medical specialty. Because few people studied the elderly, most of what we now know to be diseases of old age were viewed as the normal, inevitable, if unfortunate, consequences of aging.

The rise of Alzheimer disease as a public health problem of gargantuan proportions is a direct result of the tremendous medical advances of the 20th century. By the third decade of the 20th century, the public health was rapidly improving. Beginning in the late 1930s, anti-tuberculosis drugs and public health measures were combined to rapidly reduce deaths from that disorder. With the development of antibiotics in the 1940s and 1950s, and vaccines in the 1950s, childhood mortality fell precipitously. Over a stretch of only 50 years the median life expectancy for Americans rose by 20 years, an advance unequaled in all history and likely never to be repeated. Suddenly, many more people in the United States and Europe were living into old age. During the 1950s and 1960s, cancer, heart disease, and stroke steadily assumed much more importance on the national health agenda. Even then, dementia was largely characterized as a consequence of aging rather than as a set of distinct disorders that could be diagnosed and treated.

Although little was yet understood about it, two interesting aspects of Alzheimer disease were recognized in mid-century. A few reports of families in which many persons suffered from early onset of dementia were published in the German and English medical literature in the 1930s and 1940s, for the first time raising the issue of genetic predisposition. Furthermore, by comparing the prevalence of early disease among identical and nonidentical twins, Franz Kallman, a pioneer in the search for genetic factors in complex disorders, found strong evidence of a genetic risk. Another important advance was that neuropathologists could find no differences when they compared the lesions in the brain tissue of relatively young persons who had died with the disorder with the specimens taken from old persons. Contrary to decades of thinking that the two groups must suffer from different disorders, the evidence suggested that they both suffered from forms of the same disease.

The first crude (and unsuccessful) attempt at using linkage studies to pursue the hypothesis that Alzheimer disease may be heavily influenced by genetic predisposition was made in the late 1950s when a researcher made a long-shot bet that risk for the disorder might in some way be correlated with having a particular blood type. In 1960 there was a second unsuccessful, but poignant, effort to determine whether predisposition to the disease could be linked with having a particular blood marker among those in the MNS red cell antigen system. It was conducted by a physician who was a member of a rare family in which risk for the disorder seemed to be due to the effect of a dominant gene.

An important turning point came in 1969 when the Ciba Foundation held an international symposium to assess the status of knowledge about Alzheimer disease. This helped to reconceptualize it as a distinct disorder, not a phenomenon of aging. During the 1970s a neurologist, Robert Katz-man, who had begun studying the biochemistry of Alzheimer disease in the 1960s, emerged as a leading proponent for funding in this field. His efforts were timely. In 1974 the federal government created the National Institute of Aging (NIA). The 1970s saw a great increase in public interest in Alzheimer disease. The main reason was that the more carefully physicians and epidemiologists investigated the disorder, the larger became their estimates of its prevalence.

Interest in the use of molecular markers to find genes that predisposed to Alzheimer disease received great impetus from the stunning success in 1983 of a team led by Jim Gusella, a molecular biologist at the Massachusetts General Hospital, in mapping the gene for Huntington disease, another neurodegenerative disease, to a tiny region on the tip of chromosome 4. At the time, efforts to map disease genes by showing they must be located near established DNA markers seemed quixotic. Given the vast size of the human genome, no one thought that Gusella and his colleagues had a chance. What had seemed impossible suddenly appeared possible. When they quickly succeeded, the whole scientific world took notice. A physician-scientist named Peter St. George-Hyslop quickly took up the challenge to repeat Gusella's feat with Alzheimer disease. He arranged with Gusella to do postdoctoral studies in his laboratory so he could learn to do linkage studies. Long intrigued by the observation that virtually all persons with Down syndrome eventually develop Alzheimer disease, and knowing that persons with Down syndrome have an extra chromosome 21, St. George-Hyslop became one of a handful of people to focus his efforts on that relatively small region of the genome.

During 1985 and 1986, a team that included St. George Hyslop, a young molecular biologist named Rudi Tanzi who was constructing a critically important genetic map of chromosome 21 (and, thus, providing the markers without which a linkage study could not be attempted), and Daniel Pollen, a neurologist at the University of Massachusetts Medical School who had been gathering data and blood samples from a huge Alzheimer disease family of Russian extraction, worked furiously to investigate the hypothesis that at least one gene that predisposes to Alzheimer disease must be hidden on that chromosome. Finishing in a dead heat with three other research groups, they were able to publish strong statistical evidence for the existence of such a gene on 21 in the winter of 1987. At almost the same time, several other groups showed that a gene for a protein called "amyloid precursor protein (APP)" also mapped to chromosome 21. Since excess amyloid is the material that makes up the extracellular plaques that Dr. Alzheimer discovered in the brain cells of his deceased patients when he studied them under the microscope, the possibility that a defect in the APP gene causes at least some cases of the disease was irresistible.

In February 1991, a team led by John Hardy, a British geneticist, became the first to show that Alzheimer disease could be caused by a muta tion in a gene. He found that in one of the families in which Alzheimer disease behaved as though it were an autosomal dominant genetic disorder, there was a mutation at a certain spot in the APP gene that was always present in the DNA of affected persons and always absent in unaffected relatives. One measure of the importance of this discovery, the first irrefutable proof of why some people develop Alzheimer disease, is that their announcement became the most frequently cited paper in the entire scientific literature for that year! Only later did it become clear that this mutation accounted for an exceedingly small proportion of all cases of Alzheimer disease—about 1 in 200. Hardy's team had been studying a fascinating, but exceedingly atypical, family.

As the set of reference markers for the map of the human genome grew ever more dense during the early 1990s, the prospects of finding rare genes that predisposed to Alzheimer disease greatly improved. From 1990 to 1994, the gene mappers made tantalizing progress in finding genes that caused very rare forms of the disorder. In October 1992, a team led by Gerard Schellenberg of the University of Washington reported that in seven of nine Alzheimer families in which the disorder had very early onset, they had found strong evidence for a gene on the long arm of chromosome 14. About two years later, Schellenberg and other researchers, studying a group of families known as the Volga German kindreds (who had emigrated from the Hesse region to Russia in the 1760s and extensively intermarried), found strong evidence of linkage to another gene on chromosome 1. By 1995 the predisposing genes on both chromosomes had been cloned, and study of their proteins was under way. In both cases, however, the families that had provided the clinical information and DNA samples were, like those studied by Hardy, atypical. As recently as 1993, no one had a guess as to the location of the big gene, the one that researchers would be able to associate with increased risk for Alzheimer disease, in millions of people.


As so often happens in science, serendipity played a huge part in the next discovery. In the early 1990s, Warren Strittmayer, a biochemist who was primarily interested in cholesterol metabolism and aging, joined a team at Duke University School of Medicine led by Allen Roses, a prominent neu rologist who had for some years been especially interested in the genetics of late-onset Alzheimer disease. In 1991 a team led by Roses had reported that linkage studies with late-onset families suggested there was an influential predisposing gene on chromosome 19, but the observation did not at first generate much interest in the then relatively small Alzheimer research community, most of whose members were focusing on working out the genetics in the much less common, early-onset families. When Strittmayer heard about the statistical evidence that there was a predisposing gene somewhere on a region of chromosome 19, he realized that a gene that he had been studying that coded for a protein known as apolipoprotein E (apoE) that was involved in cholesterol transport was in the same region. Since defects in cholesterol metabolism can cause coronary artery disease and stroke, Strittmayer and Roses reasoned that a particular variant in the apoE gene might affect the brain in a way that predisposed those who had it to Alzheimer disease.

Roses quickly refined the hypothesis. In essence, he asked whether one could correlate the presence of Alzheimer disease with one of the three subtypes of apoE4 (called E2, E3, and E4) that are found among humans. The results were dramatic. He found that those individuals born with at least one copy of apoE4 (about 15% of all alleles in the population) were twice as likely to develop Alzheimer disease as were those who were born with apoE2 (about 7% of all alleles) and/or apoE3 (about 78% of all alleles). Roses' early research suggested that the 2% of the population born with two copies of apoE4 (15% times 15% is about 2%) were 9 times more likely than those with two copies of apoE3 (about 62% of the population) to develop Alzheimer disease. Furthermore, those with apoE4 appeared on average to develop symptoms at an earlier age than did those with apoE3 who developed the disorder. Roses and his team had cut the Gordian knot that everyone else had been trying to unravel. They had shown that there was a common gene variant that could explain a major portion (at least half, and perhaps as much as three-quarters) of the risk for developing Alzheimer disease in millions of people.

Once disbelief gave way to excitement, scientists rushed to test Roses' findings. In a little over two years, more than 90 studies in populations around the world proved that the association was real. As knowledge grew, it became apparent that the three slightly different proteins made by the three subtypes of the apoE gene strongly influenced the rate at which the age-related risk for Alzheimer disease grew. As Roses put it in one article, the data indicated that if humans all lived to be 140 they would all develop Alzheimer disease, regardless of their apoE status. However, the particular dyad of apoE alleles with which one was born strongly affected how early the degenerative disorder might appear. apoE4, which apparently is more efficient than is E2 or E3 in assisting the transport of the protein called amyloid into brain cells, moves one more quickly to the threshold of cellular injury at which Alzheimer disease will develop. On the other hand, if one is lucky enough to have been born with two copies of apoE2 (less than 1% of us) it appears that one's risk for early Alzheimer disease is unusually low. Persons who have two copies of apoE4 typically develop Alzheimer disease 20 years earlier than do individuals who have some combination of apoE2 and apoE3.

The Testing Dilemma

Almost overnight, knowledge about the relationship between apoE status and risk for Alzheimer disease emerged as a major ethical issue in medicine. Unlike many developments in genetics, this one involved information that could be fairly easily obtained from a well-established, widely available, low-cost test (apoE testing had been used by cardiologists studying lipid metabolism in patients with high cholesterol levels). It would be difficult, if not impossible, to curtail its use. Yet, apoE testing to assess risk for Alzheimer disease only permits one to offer a general statistical likelihood. apoE status is most definitely not tantamount to a diagnosis, nor does it approach certainty as a predictor that any particular individual will develop Alzheimer disease. Furthermore, even for a person in the highest risk group (e.g., with two copies of the E4 gene) one cannot yet responsibly hazard a guess about likely age of onset of the disease, should it develop at all.

Roses cautioned the medical community that there was no basis upon which apoE testing could be justified as a test for population-based screening or even for targeted screening in families with worrisome histories. He and others argued that its best use was to support the diagnosis in persons with discernible signs of dementia. A second possible use is to try to identify which persons with Alzheimer disease should be tried on a medicine called Tacrine, which is of questionable value but appears to slow the rate of memory loss depending on one's apoE status. During 1995 a number of papers were published that substantially agreed with his views, and in 2000 the official word on apoE4 testing is still that it should not be used to predict risk. Nevertheless, hundreds of thousands of Americans, especially those with a parent who has been diagnosed with Alzheimer disease, have asked their doctors about testing, and many thousands have been tested. The question of access to apoE testing has become a classic test case of the doctor as gatekeeper, of paternalism in medicine.

I first faced this gatekeeping test in the fall of 1995. A friend who is a successful, healthy, middle-aged accountant was struggling to care for his father during his last months with Alzheimer disease. My friend had read about apoE testing in the Wall Street Journal (which has a long history of excellent reporting on advances in medicine). When he asked his father's family practitioner about being tested, the physician had dismissed the suggestion as unlikely to yield helpful information. My friend thought differently. He wanted first to have his father tested. If his father had one or two copies of apoE4, then he wanted to be tested. He reasoned that if his father had two copies of E4 and he had only one, then his risk for developing the disorder would be lower. Similarly, if his father had one copy of E4 (as do 15% of all Americans and 50% of those with Alzheimer disease) and he had none, he could also presume that his risk was less than his father's had been.

In both instances he was correct, but he was ignoring a lot of other important facts. For example, about one-half of patients with late-onset Alzheimer disease do not carry any apoE4 alleles. Furthermore, more than half the people with one copy of apoE4 never develop Alzheimer disease (probably in many instances because they do not live long enough). Even if my friend turned out to have two copies of apoE4, the worst possible, but most predictive, scenario, it was by no means certain that he would develop the disease, nor, if he was destined to, could one predict at what age. Yet, if he did turn out to be homozygous for apoE4 might he (and perhaps others in his family) begin to think of Alzheimer disease as his destiny? What impact might that have on his mood, his self-esteem, his performance in the workplace? Would undesired test results change his low-level anxiety and reactive depression into a more serious depression?

Other issues also surfaced. Depending on how I sent the blood sample off for testing and how he decided to pay for the test, the results might or might not wind up in my friend's medical record. What implications would flow from that? If it turned out that he has two copies of apoE4 and he told this to his wife and children, how would they react? Would a report that he had one copy of apoE4 suggest to a lay person (such as a clerk at an insurance company) that he might no longer fall into the normal pool of insurable risks? Why be tested, such a person might reason, unless the results mean something? Would this compromise his ability to get disability or long-term-care insurance at standard rates? Was it proper for me, as his physician, to create a shadow chart, one that sequestered medical information from other doctors? To absolutely protect his privacy, should I (if I agreed to order it) test his sample under a pseudonym, and pay for it with a check drawn on an office account? Is there a place for anonymous testing in genetic medicine? Was I becoming paranoid?

I urged my friend not to have his father tested or to be tested himself, and he agreed, albeit reluctantly. I think he acquiesced because he did not want to raise our disagreement to the level of a confrontation. What right did I have to deny him information about himself? After all, he was not asking me to prescribe him a medicine that he did not need and that might harm him. An accountant who was far more adept at considering statistics than am I, he was asking me to help him obtain information that in the face of a positive family history might assist him in recalculating his risk for developing Alzheimer disease. What is wrong with that? The standard answer has been that most people are not sophisticated enough to assess the information they seek. Geneticists have feared that without expert counseling (and all too often, even with it), patients will misapply the information or that others will misapply it in making judgments about them. This argument is of little persuasive power to well-informed persons, nor should it be. We clearly have much to decide about how to use and how not to use predictive genetic testing.

The overwhelming opposition among human geneticists, neurologists, bioethicists, and others to using apoE testing to assess risk for Alzheimer disease that was manifest in the mid-1990s is already beginning to elicit counter-arguments. Some physicians and consumers are asserting that any test that can suggest whether or not one is at increased risk for developing a severe, late-onset disorder and, if so, on average nearly 20 years earlier than those with the standard background risk, is actually of immense value. The result can reshape a person's plans for career, retirement, estate planning, and a host of other major life issues. Between 2000 and 2003, Dr. Robert Green of Boston University School of Medicine and his colleagues at several other institutions will be studying a large cohort of persons with a family history of Alzheimer disease to determine how they respond to learning their apoE status. If the research shows that information is of value to the individuals, use of apoE testing may become more common.

Assuming that physicians decided to recommend careful use of apoE testing, they and their patients would run into another problem. A single company controls the intellectual property governing use of the test for this purpose. During the late 1990s, it was reluctant to permit other labs to license the right to test at typical industry rates. This situation (which is true for a growing number of genetic tests) constitutes an effective monopoly in which one lab sets the price of the test and forces all samples to flow to it. The implications for patients are obvious; they pay more. This is just one of a burgeoning number of intellectual property issues that will cause significant problems over the coming years and that cry for novel resolution.

Does Ronald Reagan have at least one copy of apoE4? Given his family history, I would guess that he does. Does it matter? Not yet. Someday, when we are able to fashion therapies in part keyed to genotype, it may matter a lot, but that day is still far off.

French Anderson
W. French Anderson, M.D.

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