In Pursuit of Memory Page 3
When Alzheimer showed his findings to Kraepelin the pair knew they were on to something. Clinically, Auguste’s illness seemed like a form of dementia, but the deeply bizarre and unique pattern of pathology suggested it was a distinct disease in its own right. Eager to share the discovery with the world, Alzheimer started preparing for the South-West German Psychiatrists’ meeting, which was only a few months away.
Voices murmured and chairs creaked as the growing throng of intellectual heavyweights took their seats in the old university hall. If Alzheimer was anxious about the presentation, he didn’t let it show. This was a good thing considering his audience, which included the legendary Hans Curschmann, who discovered the inherited muscle-wasting disease known today as myotonic dystrophy; Robert Gaupp, who contributed groundbreaking work on psychosis through his study of the German mass murderer Ernst Wagner; and Carl Jung, the most loyal of Sigmund Freud’s apostles and soon to be famous successor to Freudian psychology. But none of these men were as great a cause for shattered nerves as the chairman himself: Alfred Hoche, a man of unsavoury eminence who believed the mentally ill should be murdered if they offered no benefit to society (his charming ideas later extended to include the ‘racially inferior’, giving the Nazis scientific justification for their atrocities). Still, Alzheimer was confident his findings would provoke interest, and with a deep breath, he began his talk titled: ‘On a Peculiar Disease of the Cerebral Cortex’.
From a clinical perspective my Auguste D. case already offered such a distinctive clinical picture that it could not be classified among any of the known illnesses…
… her memory was most severely disturbed. If one showed her objects, she generally named them correctly, but immediately afterward she forgot everything again…
… spread over the entire cortex, especially numerous in the upper layers, one finds millet seed-sized lesions, which are characterised by the deposit of a peculiar substance in the cerebral cortex…
… Taken all in all we clearly have a distinct disease process before us.16
The silence that followed was disappointing, but not surprising. Neuroscience was still in its infancy, and scientists were busy grappling with Freud’s concepts of psychoanalysis. In fact the rest of the meeting was largely devoted to Freudian psychology, which provoked intense discussion. And though the chairman usually comes to the rescue when a speaker is put through such an embarrassment, it’s no surprise the eugenically minded Hoche kept quiet. The minutes of the meeting described Alzheimer’s talk as ‘inappropriate for a brief report’–hardly the reception it deserved.
The truth is that science has a bad reputation when it comes to accepting new ideas. As scientists, we like to think we are calm, objective, unbiased champions of the evidence. But if that evidence changes the paradigm, it often squanders the life’s work of many proud people. This is just as true today as it was back in 1906.
Alzheimer died in 1915 of heart failure at the age of fifty-one. In the years following the Tübingen meeting he continued his investigations and identified four other cases similar to Auguste. In 1910 Kraepelin acknowledged Alzheimer’s efforts in his latest psychiatry textbook, Handbook of Psychiatry, where the term ‘Alzheimer’s disease’ was used for the very first time.
The importance of Alzheimer’s work cannot be overstated. By linking the physical state of Auguste’s brain to the bewildering facts of her behaviour, Alzheimer challenged his peers to think differently. Instead of being rooted in psychology, he made it clear that dementia may reflect deeper riddles of biology. And whatever Alzheimer’s disease was, it was a riddle that cried out almost literally for a solution.
2
Understanding an Epidemic
The historian of science may be tempted to exclaim that when paradigms change, the world itself changes with them.
Thomas Kuhn, The Structure of Scientific Revolutions, 1962
IN THE DECADES that followed the eponymous Bavarian’s first public description of Alzheimer’s, scientists, pathologists and psychiatrists were at loggerheads over what he had actually discovered. Alzheimer had certainly found a unique pattern of brain pathology with those ‘peculiar’ plaques and tangles scattered among the debris of dead nerve cells.
The trouble, however, was that these so-called ‘hallmarks’ of Alzheimer’s disease were also found in the brains of people with nothing mentally wrong with them whatsoever, provided they lived long enough. In fact, post-mortems revealed that a quarter of people over the age of sixty developed plaques and tangles, despite being mentally well when they died. But Auguste Deter was only fifty-six. Was her brain undergoing some kind of accelerated ageing? If so, Alzheimer’s life’s work was on shaky ground, for one could hardly call brain ageing a ‘disease’.
And therein lay the problem. Unlike cancer, or infectious diseases such as tuberculosis and smallpox, dementia appeared to have no obvious aberration to target therapeutically, no malignant tumour or foreign pathogen to work on. It seemed as though brain cells simply withered away by their own volition. For many, this made the puzzle unsolvable. Just as the true causes of diseases were hidden by mythology and superstition during medicine’s infancy, Alzheimer’s disease was cloaked under the smokescreen of ageing.
Frustrated by this new wave of uncertainty, in the mid-1920s supporters of Alzheimer set out to confront the issue once and for all. If Alzheimer’s was really a disease, the first thing to do was pin down the symptoms. One of Alzheimer’s supporters was Ernst Grünthal, a Polish psychiatrist trained by Kraepelin and later forced to flee Germany because of his Jewish ancestry, who in 1926 described what he considered to be the most indispensible features of the disease. These included gradual memory loss, disturbance of perception, carelessness in work and appearance, disorientation as to place and time, loss of words and slurred speech, dulling of comprehension, extreme irritability, uncleanliness and disordered movements.1
But with such a motley array of symptoms it’s no surprise that Grünthal’s work didn’t stand up well. Patients often had different shades of these symptoms, and the absence of some altogether. Mindful of this, other psychiatrists suggested that Alzheimer’s and dementia were one and the same, the only difference being that the former is more severe and strikes younger than the latter. Others thought there existed multiple subtypes of Alzheimer’s disease depending on the patient’s personality and environment. Vague and arbitrary age limits for the disease started to emerge. Fifty-five was seen as the upper limit for it to be Alzheimer’s, and anything above this was dementia. In the 1940s this was raised to sixty-five and then seventy; the boundaries were so blurred no one could agree how to categorise it.
Freud’s followers seized on the paradox, using it to reassert the insignificance of biological root causes and instead stress the centrality of Freudianism. Dementia must be caused by ‘factors of a more personal nature’, said David Rothschild, an American psychiatrist trained in psychoanalysis, in 1941.2
The resulting confusion severely knocked the confidence of the Alzheimer school of thought, and threatened to send dementia research back to the dark ages during a time when psychiatric hospitals in Europe and America saw a dramatic rise in the total number of patients admitted with the disease. ‘Our institutions promise to become in time vast infirmaries with relatively small departments for younger patients with curable disorders,’ warned Richard Hutchings in his 1939 address as president of the American Psychiatric Association.
With an impending public health crisis, it became imperative to refocus the world’s attention on the problem. The time had come to parachute in a new breed of scientist.
What the hell would I want to do that for? Michael Kidd thought as he left the meeting. He had gone to discuss his latest research findings on the retina–its simple yet elegantly arranged layers of cells captivated him–and now his mentor wanted him to study brains using a complicated new tool called the electron microscope.
It was October 1961. Kidd, a physician completing neurosc
ience research at University College London, was stubbornly recalcitrant to career advice. Educated in Ashford, a small town in Kent, Kidd had joined the Royal Air Force as an operating room assistant before studying medicine and then taking a research job at the prestigious university. With his contract coming to an end, his only option now was to apply for the job at Maida Vale Hospital in north London, where they wanted to use the new technology to study a form of dementia called Alzheimer’s disease, whatever that was–he would have to look it up before the interview.3
Robert Terry was not as reluctant. Ten years older than Kidd, he had already spent several years in Paris learning how to use the microscope while training to become a pathologist. He had served during the Second World War in the 82nd Airborne Division. His colleagues described him as a ‘tough’, ‘serious’, ‘no-nonsense’ figure.4 Now, at the Albert Einstein College of Medicine in the Bronx, New York, he was eager to test the microscope on something original. Which is exactly how he saw Alzheimer’s–as an untouched challenge, something that (as far as he was aware) no one else in the field was looking at.
Standing ten feet tall and weighing half a tonne, the electron microscope looks more like the periscope of a naval submarine than a typical microscope. It’s so large it requires its own room in most laboratories. Before its invention in the 1930s, scientists depended on the light microscope, invented by the Dutch biologist Antonie van Leeuwenhoek (who used it to discover red blood cells). The light microscope gathers light from the visible spectrum using a system of lenses and can magnify objects up to 1,000 times. But the electron microscope, invented by the German physicists Ernst Ruska and Max Knoll, uses a beam of electrons and can magnify objects up to 2 million times–a 2,000-fold increase from what was previously possible. In 1937 the Hungarian physicist Ladislaus Marton began using it to take pictures of biological specimens, publishing the first EM images of bacteria. Shortly afterwards, others captured shots of fly wings, viruses and skin cells.
For Alzheimer’s research it was revolutionary. If light microscopy made brain cells look like a collection of planets in the night sky, the electron microscope provided a satellite to map the continents, mountain ranges and sprawling cities on each celestial body. The technique was firmly established in European and American laboratories just in time for Kidd and Terry to examine the detailed landscape of a brain with Alzheimer’s.
Working separately, they took samples of brain tissue from living Alzheimer’s patients and used the device to zoom in on the plaques and tangles.5 Neither knew what to expect. As they carefully focused the shower of electrons, a dark and ghostly silhouette began to creep into view. The once distant and abstruse Alzheimer plaque no longer looked like a scatter of small innocuous particles. Now it was an enormous mass of black interwoven threads, crisscrossing chaotically like a mesh of barbed wire. Whatever this was, it certainly looked capable of spreading destruction. Fragments of nerve cells lay strewn in its wake, while other cells appeared to have been pierced by shards of the dark threads themselves.
Scanning the wreckage further, the microscopists soon landed on the odd tangles of material that appeared to choke the cells from the inside. And almost immediately it was clear these were a different kind of adversary. They twisted and coiled around themselves in a strikingly ordered manner, forming curious helices much like the DNA double helix discovered by James Watson and Francis Crick only one decade earlier.
‘If you want to understand function,’ Crick famously said, ‘study structure.’ In that vein Kidd and Terry began contemplating the atomic architecture of the plaques and tangles, comparing it with what was already known about how organic molecules behave. Unknowingly, they had just formed a crucial allegiance with the blossoming field of biochemistry.
Both microscopists were in agreement that the components of the plaques closely resembled a substance called amyloid. Coined by Rudolf Virchow in 1854, amyloid derives from the Latin amylum, for ‘starch’, combined with the Greek suffix -oid, meaning ‘like’–Virchow had mistakenly identified the substance as a type of sugar. By the time Kidd and Terry began investigating, it had been discovered that amyloids are in fact composed of proteins.
Proteins are the chemical workhorses of life. Thousands of different kinds exist inside every cell in the body. Some are small and simple, performing routine tasks such as maintaining cell structure; others are large and complex, with multiple roles in tasks such as cell mobility, communication and protection from cancer. Built from a string of amino acids folded into an elaborate three-dimensional shape, proteins are the ‘actors’ of the cell while genes simply provide the ‘script’, or instructions, to create them. In other words, it is our genes that conceive of life but our proteins that construct it. But occasionally a protein will malfunction, go off radar, and settle as deposits in and around bodily organs. By the 1960s researchers started to notice an intriguing prevalence of these amyloid deposits in many disorders, including diabetes, kidney disease and certain heart conditions. Alzheimer’s, it seemed, now had to be added to the list.
What the microscopists could not agree upon, however, was the structure of the tangles. Kidd, convinced by their striking resemblance to DNA, called them ‘paired helical filaments’. Terry, on the other hand, believed each tangle to be a tube-shaped twist of material, which he called a ‘twisted neurotubule’. I, for my part, often think they could be both after seeing them in the lab. It sounds trivial, but getting the answer right was critical–it was this kind of scrutiny that helped scientists understand how viruses behave.
For the next thirteen years neither microscopist could figure out which interpretation was right. Then, in 1976, using a combination of the latest electron microscope and advancements in biochemistry, Terry discovered that Kidd was right: the tangles were indeed a strange double-helical filament similar in structure to DNA.
Knowing the shape of the tangles was important because it made it clear they were fundamentally different from the plaques, which were spherical and contained stacks of amyloid piled on top of one another like rungs on a ladder. This laid the foundation for further questions about the relation of plaques and tangles. Which came first? Did one cause the other? And are they both necessary to cause the disease?
All that had to be done now was to remove the veil of ageing. ‘Meeting the demand that senility be taken seriously involved reframing it as a scientific rather than a social problem,’ wrote science historian Jesse Ballenger. ‘Research had to be about more than the process of ageing; it had to be about something real and immediate–a dread disease.’6 In other words, it didn’t matter that Alzheimer’s was associated with ageing. It was a disease that had to be recognised and clearly defined. To do this, though, a correlation between Alzheimer’s and brain pathology had to check out: the scientists would have to prove that Alzheimer’s could be seen and measured in the brain.
This was no easy feat. The biology of brain ageing remains among the deepest mysteries in neuroscience. Healthy brains shrink and lighten by roughly 10 per cent between the ages of fifty and eighty. Some brain cells die naturally as part of this process, but most simply shrink and function more slowly–which is why elderly people can experience mild forgetfulness and occasionally have trouble with words and everyday tasks. But it’s still not clear why plaques and tangles can also accumulate during normal ageing. The greatest conundrum for early researchers, therefore, was how to square the fact that some people developed plaques and tangles while remaining Alzheimer’s-free.
In 1966 an English research group at Newcastle University, led by Hungarian-born Martin Roth, devised a study to do just that. Roth believed that the main reason early attempts to link the plaques and tangles to the physical manifestation of Alzheimer’s had failed was because we’d been approaching the problem in the wrong way. Performing post-mortems on brains first and then retrospectively trying to piece together a clinical picture of the patient while they were still alive was, he said, erroneous. It was also unscientific
: the clinical picture of Alzheimer’s patients was based on hospital notes, written by people who, despite their best efforts, would inevitably paint different pictures of the same patient. A more objective method was needed, one that could accurately measure a suspected case of Alzheimer’s during life, follow the brain to post-mortem, and only then look for any biological correlations.
He recruited the help of pathologist Bernard Tomlinson and psychiatrist Gary Blessed, both of whom, like Roth, thought that dementia was being ignored largely because the methods for defining it were unsophisticated. The trio began by devising a ‘dementia score’: a test for assessing a patient’s cognitive ability. Every six months they asked a patient’s close relative to score their loved one on a battery of questions involving everyday habits, domestic tasks, personality changes and memory. For instance, how able were they to cope with small sums of money? Or remember lists of items on a shopping list? Could they eat and get dressed unaided? Did they remember the date of the Second World War? Or who the current Prime Minister was? Crucially, the study included elderly patients who were deemed cognitively normal in order to find out which symptoms were linked to Alzheimer’s and which were just old-age forgetfulness. Once the brains came to post-mortem, the researchers counted the plaques, comparing the severity of plaque burden with the dementia scores they had collected over the final years of a patient’s life.
The results spoke for themselves: there was an irrefutable connection between dementia scores and plaque count. The higher the former–you guessed it–the greater the latter. In a landmark paper published in Nature, Roth, Tomlinson and Blessed declared that, ‘Far from plaques being irrelevant for the pathology of old-age mental disorder, the density of plaque formation in the brain proves to be highly correlated with quantitative measures of intellectual and personality deterioration in aged subjects.’7