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
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