The Forgetting: Understanding Alzheimer’s: A Biography of a Disease

Alzheimer’s disease overtakes a person very gradually, and for a while can be indistinguishable from such mild memory loss. But eventually the forgetting reaches the stage where it is quite distinct from an absentminded loss of one’s glasses or keys. Fleeting moments of almost total confusion seize a person who is otherwise entirely healthy and lucid. Suddenly, on a routine drive home from work, an intersection he has seen a thousand times is now totally unfamiliar. Or he is asking about when his son is coming back from his vacation, and his wife says: “What do you mean? We both spoke to him last night.” Or he is paying the check after a perfectly pleasant night out and it’s the strangest thing, but he just cannot calculate the 20 percent tip.

The first few slips get chalked up to anxiety or a lousy night’s sleep or a bad cold. But how to consider these incidents of disorientation and confusion when they begin to occur with some frequency? What begin as isolated incidents start to mount and soon become impossible to ignore. In fact, they are not incidents; collectively, they are signs of a degenerative condition. Your brain is under attack. Months and years go by. Now you are losing your balance. Now you can no longer make sense of an analog clock. Now you cannot find the words to complain about your food. Now your handsome young husband has disappeared and a strange elderly man has taken his place. Why is someone taking your clothes off and pouring warm water over you? How long have you been lying in this strange bed?

By 1992, the signs of Reagan’s illness were impossible to ignore. At the conclusion of a medical exam in September, as the New York Times would later report, Reagan looked up at his doctor of many years with an utterly blank face and said, “What am I supposed to do next?” This time, the doctor knew that something was very wrong.

Sixteen months later, in February 1994, Reagan flew back to Washington, D.C., from his retirement home in Bel Air, California, for what would turn out to be his final visit. The occasion was a dinner celebrating his own eighty-third birthday, attended by Margaret Thatcher and twenty-five hundred other friends and supporters.

Before the gala began, the former President had trouble recognizing a former Secret Service agent whom he had known well in the White House. This didn’t come as a total shock to his wife, Nancy, and other close friends, but it did cause them to worry that Reagan might have problems with his speech that night.

The show went on as planned. After an introduction by Thatcher, Reagan strolled to the podium. He began to speak, then stumbled, and paused. His doctor, John Hutton, feared that Reagan was about to humiliate himself. “I was holding my breath, wondering how he would get started,” Hutton later recalled, “when suddenly something switched on, his voice resounded, he paused at the right places, and he was his old self.”

Back at his hotel after the dinner, Reagan again slipped into his unsettling new self, turning to Nancy and saying, “Well, I’ve got to wait a minute. I’m not quite sure where I am.” Though the diagnosis and public announcement were both months away, Reagan was already well along the sad path already trod by his mother, his brother, and by Auguste D.

The doctors who diagnosed Reagan in 1994 knew with some specificity what was happening to his brain. Portions of his cerebral cortex, the thin layer of gray matter coating the outside of his brain, were becoming steadily clouded with two separate forms of cellular debris: clumpy brown spherical plaques floating between the neurons, and long black stringy tangles choking neurons from inside their cell membranes. As those plaques and tangles spread, some neurons were losing the ability to transmit messages to one another. Levels of glucose, the brain’s sole energy source, were falling precipitously, weakening cell function; neurotransmitters, the chemicals that facilitate messages between the neurons, were becoming obstructed. The tangles in some areas of the brain were getting to be so thick it was like trying to kick a football through a chain-link fence.

Ultimately, many of the neurons would die, and the brain would begin to shrink. Because the brain is highly specialized, the strangulation of each clump of neurons would restrict a very specific function—the ability to convert recent events into reliable memories, for example, or the ability to recall specific words, or to consider basic math problems. Or, eventually, to speak at all, or recognize a loved one. Or to walk or swallow or breathe.

We know about plaques and tangles because of Auguste D. and Alois Alzheimer. After four and a half years in the hospital, Frau D. died on April 8, 1906. Her file listed the cause as “septicaemia due to decubitis”—acute blood poisoning resulting from infectious bed sores. In her last days, she had pneumonia, inflammation of the kidneys, excessive fluid in the brain, and a high fever. On the day of her death, doctors understood no more than they had on the first day she was admitted. They could say only this about Auguste D.: that a psychic disturbance had developed in the absence of epileptic fits, that the disturbance had progressed, and that death had finally intervened.

Alois Alzheimer wanted to learn more. He wanted to look at her brain.

Standing apart from most doctors at the time, Alzheimer was equally interested in both clinical and laboratory work. He was known for his tireless schedule, his devoted teaching, and his own brand of forgetfulness. An inveterate smoker, he would put a half-smoked cigar down on the table before leaning into a student’s microscope for a consultation. A few minutes later, while shuffling to the next microscope, he’d light a fresh cigar, having forgotten about the smoke already in progress. At the end of each day, twenty microscopes later, students recalled, twenty cigar stumps would be left smoldering throughout the room.

But Alzheimer did not forget about the woman who had lost herself in Frankfurt. Though he had since moved to the Royal Psychiatric Clinic, in Munich, to work for the renowned psychiatrist Emil Kraepelin, he sent for Frau D.’s central nervous system as soon as she died. Her brain, brainstem, and spinal cord were gently removed from the elaborate bone casing, that flexible yet durable wrapper that allows us all to crouch, twist, and bump into things without much concern. The exposed contents were then likely wrapped in formalin-soaked towels, packed carefully in a wooden crate, and shipped by locomotive 190 miles southeast to Munich.

Imagine, now, that lifeless brain on a passenger train. A coconut-sized clump of grooved gelatinous flesh; an intricate network of prewired and self-adapting mechanisms perfected over more than a billion years of natural selection; powered by dual chemical and electrical systems, a machine as vulnerable as it is complex, designed to sacrifice durability for maximal function, to burn brightly—a human brain is 2 percent of the body’s weight but requires 20 percent of its energy consumption—at the cost of impermanence. Enormously powerful and potato-chip fragile at the same time, the brain is able to collect and retain a universe of knowledge and understanding, even wisdom, but cannot hold on to so much as a phone number once the glucose stops flowing. The train, an elementary device by comparison, can, with proper maintenance, be sustained forever. The brain, which conceived of the train and all of its mechanical cousins, cannot. It is ephemeral by design.

But there was nothing in the brain’s blueprint about this sort of thing, as far as Alzheimer could infer. This was a flaw in the design, a molecular glitch, a disease process, he suspected, and it was important to see what that process looked like up close.

It was also now actually possible to do this for the first time, thanks to a whirl of European innovation. Ernst Leitz and Carl Zeiss had just invented the first distortion-free microscopes, setting a standard in optics that survives today. Franz Nissl had revolutionized tissue-staining, making various cell constituents stand out, opening up what was characterized as “a new era” in the study of brain cells and tissues. (The “Nissl method” is still in use. Nissl, a close collaborator and friend of Alois Alzheimer, became a medical school legend with his instructions on how to time the staining process. “Take the brain out,” he advised. “Put it on the desk. Spit on the floor. When the spit is dry, put the brain in alcohol.”)

Dr. Alzheimer’s assistants prepared for microscopic examination more than 250 slides from slivers of the outer lining (the meninges) of Frau D.’s brain; from the large cerebral vessels; from the frontal, parietal, and occipital areas of the cerebral cortex (locus of conscious thought); from the cerebellum (regulator of balance, coordination, gait) and the brainstem (breathing and other basic life functions); and from the spinal cord, all chemically preserved in a cocktail of 90 percent alcohol/10 percent formalin, and stained according to a half-dozen recipes of Alzheimer’s contemporaries.

Having fixed, frozen, sliced, stained, and pressed the tissue between two thin pieces of glass, Alzheimer put down his cigar and removed his pince-nez, leaned into his state-of-the-art Zeiss microscope, and peered downward. Then, at a magnification of several hundred times, he finally saw her disease.

It looked like measles, or chicken pox, of the brain. The cortex was speckled with crusty brown clumps—plaques—too many to count. They varied in size, shape, and texture and seemed to be a hodgepodge of granules and short, crooked threads, as if they were sticky magnets for microscopic trash.

The plaques were nestled in amongst the neurons, in a space normally occupied by supporting tissue known as glial cells. They were so prominent that Alzheimer could see them without any stain at all, but they showed up best in a blend of magenta red, indigo carmine, and picric acid. Alzheimer had squinted at thousands of brain slides, but he found these clumps “peculiar” and had no idea what they could be.

A different stain, invented just four years earlier, revealed the other strange invasion of Auguste D.’s brain. In the second and third layers of the cortex, nearly a third of the neurons had been obliterated internally, overrun with what Alzheimer called “a tangled bundle of fibrils”—weedy, menacing strands of rope bundled densely together.

The tangles were just as foreign to Alzheimer as the plaques, but at least the ingredients looked familiar. They seemed to be composed of fibrils, an ordinary component of every neuron. It was as if these mild-mannered, or “Jekyll,” fibrils had swallowed some sort of steroidal toxin and been transformed into “Hyde” fibrils, growing well out of proportion and destroying everything within their reach. Many affected neurons were missing a nucleus completely, and most of the rest of their cell contents. A good portion of the neurons in the upper cell layers of the cortex had disappeared. They just weren’t there. Alzheimer’s assistant Gaetano Perusini wrote of the neurofibrillary tangles in Frau D.’s brain:

It is impossible to give a description of all the possible pictures: there are present all the variable and twisted formations that one can imagine; at times large fibrils seem to lie only on the periphery of the cell. But on focusing untangled fibrillar agglomerations are found. Changing the focus again one has the impression that the single dark-coloured fibrils unwind into an infinite number of thinner fibrils … arranged as balls of twine or half-moons or baskets.

Connecting a camera lucida to the top of the microscope, Alzheimer and Perusini both drew pictures of the tangles.

The menacing drawings perfectly convey the ghastly significance of their discovery. Here was the evidence that Auguste D. had not lost herself. Rather, her “self” was taken from her. Cell by cell by cell, she had been strangled by unwelcome, malignant intruders.

What were they, exactly, and where did they come from?

When my kids began to say they were worrying about my memory, I said to them, “Well, I’ve never had a photographic memory, and I have a lot more on my mind now. There’s a lot more to remember with life being so complex. How can I remember everything? What do you want—total recall?” I always had an answer. I really was in denial, and it just didn’t occur to me that I had a problem. But I also knew that they weren’t totally exaggerating.

—D.

New York, New York

Chapter 2 BOTHERED

Queens, New York: August 1998

It was lunch time in Freund House, in the village of Flushing. A small group of elderly Jews sat quietly at a round table. Not much was said as they ruffled open their brown paper bags and popped the lids off drinks. Someone brought in a big bottle of ginger ale and some plastic cups, and offered to pour.

Irving looked over at Greta and noticed that she was sitting still, her hands folded together on the bright red table cloth.

“Did you bring your lunch today, Greta?”

“I don’t think so. I usually don’t bring my lunch here.”

“Yes, you do. You bring cereal.”

Irving waited for Greta to recollect her routine, but she could not. An elegant, shrunken woman with short cropped hair, dark eyebrows, and a supple, leathery face, Greta did not look even remotely like someone in decline. Her eyes still sparkled and her voice had spunk. She spoke without hesitation and in full, clear sentences. There was no clue from her cadences that her brain was under attack.

Paying close attention, though, one could tell that something was not right. For example, in a conversation about Japan, Greta very clearly explained that she had been there a number of times. She discussed the temples of Kyoto, which she enjoyed, and the food, which she did not.

Then, about an hour later, the subject of Japan came up again. This time, she said matter-of-factly, “Japan—never did get there. Couldn’t get in.”

These hiccups in logic were typical, I now recognized, of someone beginning to advance past the very earliest stages of the disease. She wasn’t very far along yet, and most of her brain was still working quite well; but her symptoms were no longer strictly limited to the classic short-term memory loss that usually signals the disease’s onset. Occasionally, now, a queer incongruity would creep in.

Standing off to one side of the table was Judy Joseph, the co-leader, with Irving Brickman, of this support group. About a year earlier she had been introduced to Irving in the New York offices of the Alzheimer’s Association, where each had come to see what, if anything, could be done about this ominous new social phenomenon. Suddenly, it seemed, Alzheimer’s disease was everywhere. Nursing home dementia units were filling beyond capacity. Middle-aged children were moving back home to take care of their parents. Community police were regularly being phoned to help track down wandering relatives. The disease was cropping up continually in newspaper articles and everyday conversation. Perhaps most tellingly, a vibrant Alzheimer’s consumer market was springing up—products like automatic medication dispensers (no memory required!), wireless tracking devices for wanderers, and even a Stovetop fire extinguisher designed explicitly for people who might forget to turn off the range.

All of a sudden, everyone seemed to know someone touched by Alzheimer’s. Partly, this was due to a shift in public conception of senile dementia. Only in the mid-1970s had doctors started to realize that senility is not an inevitable process of brain aging and decay but a recognizable—and perhaps one day treatable—disorder. Gradually, this perception also started to seep into the general consciousness: Senility is a disease.

Since then, there had been a staggering rise in actual cases of Alzheimer’s, corresponding to a vast increase in the elderly population. People were now living much longer lives. Longer lives meant more cases of Alzheimer’s. Since 1975, the estimated number of Alzheimer’s cases in the U.S. had grown tenfold, from 500,000 to nearly 5 million. Worldwide, the total was probably about three times that figure. In the absence of a medical breakthrough, the gloomy trend would not only continue, but would also get much, much worse.

The Roman poet Virgil wrote in the first century B.C., “Time wastes all things, the mind, too.” He was partly right. Scientists do not believe that Alzheimer’s is an inevitable consequence of aging. Many people will never get the disease regardless of how long they live. But aging is by far the greatest risk factor. It is almost unheard of in people aged 20–39, and very uncommon (about one in 2,500) for people aged 40–59. For people in their sixties, the odds begin to get more worrisome. An estimated and so on have Alzheimer’s or a closely related dementia. The risk accelerates with age, to the point where dementia affects nearly half of those eighty-five and over.

• 1 percent of 65-year-olds

• 2 percent of 68-year-olds

• 3 percent of 70-year-olds

• 6 percent of 73-year-olds

• 9 percent of 75-year-olds

• 13 percent of 77-year-olds

So, as the twentieth century came to a close, a shadow legacy was rapidly becoming apparent—the dark, unintended consequence of the century’s great advances in hygiene, nutrition, and medicine. Life spans in industrialized nations had nearly doubled over the previous one hundred years, and the percentage of elderly among the general population had more than tripled. In the process, the number of cases of senile dementia mushroomed. A hundred years before, it had not even been a statistical blip. Paradoxically, in the full blush of medical progress of the twentieth century, it had blossomed into a major public health problem.

Most strikingly to social workers like Judy and Irving, the number of people who had Alzheimer’s and who knew they had Alzheimer’s had exploded. A huge portion of the newly diagnosed cases were in the very early stages of the disease. “This is something new in the field,” Irving explained. “Most people never before realized that there is an early stage of Alzheimer’s. I had worked with the more advanced stages, but when I came into this it was overwhelming for me. It’s very hard to get used to a normal person who happens to have dementia. It’s a whole different ballgame.”

Judy and Irving recognized, along with many others in the national Alzheimer’s community, that something had to be done to help this emerging new constituency: early-stage dementia sufferers still functioning well enough to fully understand what lay ahead. With the assistance of the Alzheimer’s Association, they formed a support group at Freund House. “Our goal,” explained Irving, “is to try to help these people live a quality life, to help them gain some coping mechanisms for their deficits, and to help them feel better as human beings.” While scientists did battle with this disease, victims and their families had the opposite task: to make a certain peace with it, to struggle to understand the loss, come to terms with it, create meaning out of it.

Alzheimer’s is what doctors call a disease of “insidious onset,” by which they mean that it has no definitive starting point. The plaques and tangles proliferate so slowly—over decades, perhaps—and silently that their damage can be nearly impossible to detect until they have made considerable progress. Part of the function of any early-stage support group must be to try to make sense of this strange new terrain that lies between healthy and demented. Where, in specific behavioral terms, is the person overshadowed by the disease?

Individually and collectively, the Freund House group was trying to find out, and to make sense of the answer. “My wife gets frustrated with me,” Arnie related to his fellow group members, “and she is right to be frustrated. She asks me to put a can in the recycling … and I don’t do it. She says, ‘I know this is because of your illness, that this is not you.’”

Sadie nodded her head in recognition. “My mother had this, too,” she said. “Now I know what it was like for my father to take care of her. We used to get so mad at him when he would be short with her.”

Coping with a particular disability was one thing; trying to cope with an ever-shifting invisible illness, though, was a challenge unique to Alzheimer’s disease. In this early period, the insidiousness itself was often the most troubling thing about the disease—arguably even a disease unto itself As a group, these new patients could gain a more confident understanding of their disease, and tackle issues that would seem impossibly difficult to one isolated, failing person.

Driving, for instance. The first big question they confronted right after forming the group was: Should they continue, in this blurry period of semi-normalcy, to pilot massive steel boxes at thirty and forty and fifty miles per hour down roads lined with bicycles and toddlers? Studies showed conclusively that Alzheimer’s is, overall, a major driving hazard. Bystanders had been killed by Alzheimer’s patients making a lapse in judgment or being overcome momentarily by confusion. But the law had not yet caught up with this reality. Even with a diagnosis, no doctor or judge had ever confiscated a license. Families were forced to decide on their own when driving was no longer appropriate.

Together, after much deliberation, the group decided that it had already become too dangerous. Collectively, they gave up this highly charged symbol of autonomy and competence. On this shaky new terrain, a person’s independence could no longer be taken for granted.

In the summer of 1984, at the age of eighty-five, E. B. White, the tender essayist and author of Charlotte’s Web, became waylaid by some form of dementia. It came on very swiftly. In August, he began to complain of some mild disorientation. “We didn’t pay much attention,” recalls his stepson, Roger Angell, “because he was a world-class hypochondriac.” But just a few weeks later. White was severely confused much of the time. By the following May, he was bedridden with full-on dementia, running in and out of vivid hallucinations and telling visitors, “So many dreams—it’s hard to pick out the right one.” He died just a few months after that, in October 1985.

An obituary in the New York Times reported White as having Alzheimer’s disease, but that appeared to miss the mark. In fact, he was never even informally diagnosed with the disease, and his symptoms strongly suggested another illness. The rapid onset of the confusion and the abrupt shift from one stage to the next were classic signs of multi-infarct dementia, the second-most common cause (15 percent) of senile dementia after Alzheimer’s (60 percent). Multi-infarct dementia is caused by a series of tiny strokes. Its victims can have much in common with those of Alzheimer’s, but the experience is not as much of an enigma. Its cause is known, somewhat treatable, and, to a certain extent, preventable (diet, exercise, and medication can have an enormous impact on risk of strokes). Its jerky, stepwise approach is easier to follow and understand as symptoms worsen.

Alzheimer’s disease is not abrupt. It sets in so gradually that its beginning is imperceptible. Creeping diseases blur the boundaries in such a way that they can undermine our basic assumptions of illness. Alzheimer’s drifts from one stage to the next in a slow-motion haze. The disease is so gradual in its progression that it has come to be formally defined by that insidiousness. This is one of the disease’s primary clinical features, one key way that Alzheimer’s can be distinguished from other types of dementia: those caused by strokes, brain tumor, underactive thyroid, and vitamin deficiency or imbalance in electrolytes, glucose, or calcium (all treatable and potentially reversible conditions).

It is also nearly impossible to officially diagnose. A definitive determination requires evidence of both plaques and tangles—which cannot be obtained without drilling into the patient’s skull, snipping a tiny piece of brain tissue, and examining it under a microscope. Brain biopsies are today considered far too invasive for a patient who does not face imminent danger. Thus—Kafka would have enjoyed this—as a general rule, Alzheimer’s sufferers must die before they can be definitively diagnosed. Until autopsy, the formal diagnosis can only be “probable Alzheimer’s.”