In Pursuit of Memory

by Joseph Jebelli

  More importantly, they found that ageing alone was not enough to explain the number of plaques seen in Alzheimer’s patients. With an air of modesty that now seems overly cautious, they ended their report by asserting that: ‘The facts suggest that [plaques] and related processes may also deserve investigation with the aid of more precise techniques than those employed in this study.’

  The twentieth-century philosopher of science Thomas Kuhn observed that great scientific discoveries seldom occur in a steady, stepwise fashion. Instead, he said, they happen in ‘paradigm shifts’, in which ‘one conceptual world view is replaced by another’.8 Kidd and Terry’s probing microscopy work, combined with Roth, Tomlinson and Blessed’s great unveiling of a disease, did that for dementia. By depicting plaques and tangles in sharp relief against the rest of the brain, and combining innovation with careful examination and good science, they brought about a radical rethink in how we should define and approach the problem. They made it clear that people with Alzheimer’s were suffering from an affliction no less urgent than cancer or stroke. And if people with other diseases of old age deserved recognition and action, then so did people with Alzheimer’s. They had elevated a pursuit long considered futile.

  Soon others started to speak out, including the physician and scientist Robert Katzman who, inspired by his mother-in-law’s battle with the disease, became a staunch and leading activist for Alzheimer’s research. In a historic editorial published in 1976 in the Archives of Neurology, titled ‘The prevalence and malignancy of Alzheimer’s disease’, he argued that the time had come to stop thinking of Alzheimer’s and dementia as separate disease entities.

  ‘Neither the clinician, the neuropathologists, nor the electron microscopist can distinguish between the two disorders, except by the age of the patient,’ Katzman wrote. ‘We believe it is time to drop the arbitrary age distinction and adopt the single designation, Alzheimer’s disease.’9 In this context, he proposed that Alzheimer’s was a biological affliction that occurred along an age continuum. Rare cases appeared in middle age to sixty, with a predictably increasing likelihood for every ten years thereafter.

  Many scientists agreed, and this new acceptance highlighted Alzheimer’s as ‘a major killer’–the fourth leading cause of death in America alone–and something far more ominous than previously thought. With the world’s population steadily ageing, Alzheimer’s could now be seen for what it truly is: a global and inescapable epidemic.

  3

  A Medicine for Memory

  All life is chemistry.

  J. B. van Helmont, Ortas Medicinae, 1648

  ON 5 NOVEMBER 1986, in a proclamation to raise awareness for Alzheimer’s, President Ronald Reagan addressed the crowd: ‘No cure or treatments yet exist… but through research we hope to overcome what we now know is a disease…’1 For the scientists who had worked for so long to prove that Alzheimer’s is not a normal part of ageing, this public recognition of the Alzheimer’s epidemic was a landmark moment. Three years earlier, President Reagan had declared November as America’s National Alzheimer’s Disease Month. Reagan would himself later succumb to Alzheimer’s.

  On the same November day in 1986, the office of William Summers, a neuroscientist at the University of Southern California, Los Angeles, was flooded with telephone calls from the press. They had in their possession an advance copy of the New England Journal of Medicine article that Summers was about to publish, which, he claimed, demonstrated a treatment for Alzheimer’s disease.

  Recent attempts to understand the brain have mainly involved breaking it down into its constituent parts, examining those parts, and then fitting them into a larger theoretical framework–a philosophy known as reductionism. Though many now believe it’s time to move on from this way of thinking because the brain is proving more complicated than the sum of its parts, reductionism has provided us with an enormous amount of knowledge, upon which much of the research into a cure for Alzheimer’s has relied.

  Broadly speaking, the brain is composed of two main cell types–neurons and glia. Neurons, the nerve cells of the brain, are electrical cells that send chemical messages to one another at specialised contact points called synapses. They are often compared to trees in a dense forest or wires in a telecommunications network. You could also think of them as the masters of social media: each neuron is like a person that has around 85 billion ‘friends’, and they are part of a ‘network’ of synaptic connections that is 100 trillion strong. This means that every second, billions of neurons are sending trillions of synaptic messages in the deepest recesses of your mind.

  Glia (Greek for ‘glue’) are non-electrical cells that protect and support neurons. It was thought they did little else–hence the disparaging Greek translation. But there is now good evidence that glia command far more illustrious roles in the brain, and swathes of neuroscientists on the front lines of Alzheimer’s research are busy deciphering those roles in a bid to exploit them therapeutically.

  According to the British biologist Lewis Wolpert, the best way to appreciate a neuron’s complexity is to imagine each is the size of a human. At this scale the whole brain would cover an area of ten kilometres, nearing the size of Manhattan–and ten kilometres into the sky. The population of Manhattan is around 1.6 million people, but this space would be occupied by billions of ‘neuron-people’ piled high on top of one another, each one talking to between 100 and 1,000 of its neighbours.2 If you can imagine that, then you can get a sense of how sophisticated the neuron is.

  A typical neuron is composed of a cell body, numerous fine projections called dendrites, and one long projection called the axon. Several ‘internal organs’, or organelles, exist inside the cell body–such as the nucleus, which houses the neuron’s DNA, the mitochondria, which provide the neuron with energy, and the ribosomes, which act as microscopic protein factories. Closely spaced along the length of the dendrites are the synapses, each one making contact with another neuron by almost touching the terminal of its axon. In this way neurons form a fixed but highly dynamic web of interactions.

  Major components of a neuron

  Zooming out from this level, the brain is held together in distinct anatomical units, like pieces of glass in a stained-glass window. Each unit takes on the duty of controlling different functions.3 The medulla oblongata, for instance, is located at the base of the brainstem and performs the onerous task of regulating heart rate, blood pressure and breathing. The cerebellum, just above the brain stem, helps coordinate movement. The thalamus, buried deep within the centre of the brain, controls sleep and wakefulness. The cerebral cortex, that eye-catching folded outer layer of the brain, gives rise to the higher human faculties, such as language, emotion and consciousness. And the hippocampus (Greek for ‘seahorse’), one of the very first regions to succumb to Alzheimer’s, plays a pivotal role in converting short-term memory to long-term memory.

  Examples of just a few brain regions

  Neurotransmitter release at the synapse

  The brain works by constantly transmitting chemical messages across synapses. When such a message is delivered, the neuron is said to have ‘fired’, resulting in countless different processes–from making sure you continue to breathe to ensuring your fingers do what you tell them to do. We call these messages neurotransmitters and most come in the form of chemical compounds. Glutamate, for instance, is a major neurotransmitter. Acetylcholine is another.

  The signals these molecules convey form the roots of many aspects of normal brain function: emotion, learning, memory. While pinpointing a thought’s origin in the brain is like deciding where a forest begins, thoughts are essentially generated by neurons triggering the release of neurotransmitters. It comes as no surprise, then, that scientists in the 1970s turned their heads when a striking loss of the neurotransmitter acetylcholine was seen in the brains of Alzheimer’s patients.

  It was 1978 and, almost simultaneously, three groundbreaking studies by separate teams of British biochemists were changing
the face of Alzheimer’s research: one led by Peter Davies at Edinburgh University;4 the second by Elaine and Robert Perry at Newcastle University;5 the third by David Bowen at the London Institute of Neurology.6

  The 1970s were a fertile decade for dementia awareness. In America, Florence Mahoney, a prominent health activist, began lobbying politicians to create a new institute that specialised in age-related disorders to complement the already existing National Institute of Health (NIH). With her help, Congress convinced President Nixon to pass the Research on Aging Act of 1974, and a National Institute on Aging (NIA) was established. In the UK, health activist Peter Campbell founded the Mental Patients’ Union (MPU), which campaigned against the then asylum-based psychiatric system that had been repeatedly exposed as a source of neglect and abuse for people with dementia,7 and in 1979 a small group of patient relatives and prudent medical practitioners formed the Alzheimer’s Disease Society (known today as the Alzheimer’s Society). Across Europe, prestigious academic institutes–in Berlin, Paris, Rome and Stockholm–began to bring together scientists from diverse backgrounds and establish university departments with the sole purpose of unearthing the disorder’s unknown origins.

  In Britain, the biochemists had noticed a mysterious link between the effects of a childbirth anaesthetic and memory formation. From the turn of the century until the 1960s, a drug called scopolamine was used to spare mothers the pain of childbirth. Before that, chloroform had been the only option, but it was widely rebuked in the medical establishment as the source of life-threatening complications such as heart failure. Scopolamine, derived from the Asian flowering plant Scopolia tangutica, signified progress for its capacity to induce a ‘Twilight Sleep’: a state where the patient felt no pain while simultaneously remaining completely awake. More striking, though, was the intriguing observation that mothers often emerged from the treatment with no memory of their birthing experience whatsoever. No one could explain it. But what scientists did know was that scopolamine disrupted acetylcholine signalling in the nervous system.

  Pinning down the neurochemistry of how memories are formed was, and remains, a Holy Grail for neuroscience. We still don’t know how memory works. In the 1970s the Norwegian scientists Per Anderson and Terje Lømo had offered the most convincing theory to date. They argued that memories are made and lost by a respective strengthening and weakening of neuronal synapses. They called their model ‘long-term potentiation’ (LTP).8 The phenomenon occurs, they said, after a synapse receives a high-frequency electrical stimulation. This causes a long-lasting increase in the strength of connections between neurons. Like almost everything in science, the truth (or in this case, the hypothesis) is almost too strange to comprehend, but Anderson and Lømo suggested that those connections–simply put–are our memories. They are nothing like how we perceive them to be–images and feelings passing through our minds. Memories are physically encoded.

  So when a memory is born, say, from meeting someone for the first time, the information is first sent to the hippocampus to be encoded in a network of synapses. Some of this information will linger here as short-term memory, which lasts around thirty seconds, but if something about the meeting is important or has a strong emotional element, then the information is channelled to synapses in the cortex where it resides as long-term memory. If the science here sounds imprecise and unsatisfactory, that’s because it is. We know that long-term memory can be divided broadly into declarative and procedural. Declarative memory refers to knowledge gathered over a lifetime, like the name of your dog, or how many children you have. Procedural memory involves remembering how to do certain things, like tying shoelaces, or driving a car. But in terms of memory’s underlying neurophysiology, Anderson and Lømo’s theory of LTP, combined with the observation that neurotransmitter signalling is somehow involved, was (and still is) the best description of memory in neuroscience.

  With that, the British biochemists immediately asked the obvious question: could acetylcholine loss be the key to the decline in memory seen in Alzheimer’s disease? It was a highly attractive theory. If proven true it could collapse the entire puzzle into a single piece: scientists would be able to develop a drug that simply replaces the acetylcholine. Indeed, Parkinson’s research had triumphed this way in the 1960s, when a loss of the neurotransmitter dopamine was identified and scientists discovered a way to replace it using the drug Levodopa. Though not curative, the therapeutic gain for Parkinson’s patients has been remarkable.

  But in the case of Alzheimer’s the answer was not so straightforward, and the success of the idea depended upon a number of questions. The first: was there a reduction in acetylcholine found in brain samples from deceased Alzheimer’s patients? After an extensive search of post-mortem tissue the British groups were in unanimous agreement, and by 1978 all had published their findings. ‘Yes’, it appeared.

  The next question: could artificially blocking acetylcholine in young healthy people trigger the same kind of memory loss seen in the elderly? As luck would have it this question had already been answered. In 1974 David Drachman and Janet Leavitt at Northwestern University, Chicago, took a group of young student volunteers, gave them a dose of ‘Twilight Sleep’ using scopolamine, and tested their ability to store and retrieve new memories.9 Could they, for example, remember and repeat a random sequence of numbers after listening to them on a tape recorder? And how many nouns could they list that were categorised as animals, fruits and girls’ names? They then gave the same tests to healthy volunteers aged between fifty-nine and eighty-nine who had not been given the drug. Astonishingly, while the untreated students far outperformed the elderly subjects in every test, the students under the influence of scopolamine performed just as poorly as their elderly counterparts. Here again, the answer was an affirmative.

  The final question–and indeed the most crucial–was: does boosting acetylcholine release in the brains of living Alzheimer’s patients improve their memory? The simplest way to test this was dietary. To make acetylcholine, neurons first need choline, a vitamin found circulating in the blood. The vitamin is provided in significant amounts from the food we eat–eggs, beef and fish, for instance, are plentiful in choline.

  From 1978 to 1982 a number of European and American clinical trials tested the effect of dietary choline supplements on Alzheimer’s patients.10 They used doses up to fifty times the average human intake, gave it every day for months at a time, tested hundreds of patients of different ages, and implemented dozens of new methods for assessing memory and cognitive ability. The trials were the culmination of a collective effort of more than a dozen studies performed by a total of nearly 100 of the world’s leading scientists. It hailed the first milestone in translating the findings of basic research into a real-world therapy for Alzheimer’s. And it marked a new precedent in the history of humanity’s response to the disease.

  But it failed. The results of almost every study reported no effects on memory and no improvement on any tests of cognition. While a few groups declared some benefit, the data backing up such claims was inadequate. Whatever the reason, neurons had given up making acetylcholine, and giving them copious amounts of choline in the hope they would kick-start the mechanism back into action wasn’t enough.

  But all was not lost. ‘Truth in science,’ the Austrian zoologist Konrad Lorenz said, ‘can be defined as the working hypothesis best suited to open the way to the next better one.’ What if, some scientists asked, instead of trying to make new neurotransmitter from scratch, we simply kept the acetylcholine that was already present in the brain around for longer?

  On the evening of 16 March 1988 huge clouds of yellow smoke began to rise into the air in the small city of Halabja, in the foothills of the Hawraman Mountains in Iraqi Kurdistan. Confused families rushed indoors and into basements; others ran into their cars and closed the windows. What they saw defied belief. In the streets among the smoke, crowds of people were uncontrollably vomiting, urinating and defecating, before violently convulsing and
falling to the ground in seizures. The attack left an estimated 5,000 people, mostly civilians, dead, massacred by Saddam Hussein’s forces in the final days of the Iran–Iraq war. The weapon of choice was a deadly chemical nerve gas known as sarin.

  Sarin is twenty times more toxic than cyanide. It works by meddling with the neurotransmitter acetylcholine. Specifically, it binds to and paralyses another protein, called acetylcholinesterase, responsible for degrading acetylcholine. This causes a build-up of excess neurotransmitter, which wreaks havoc on the nervous system because acetylcholine signalling is also responsible for controlling muscle contraction. As a result the victim experiences a grotesque and undignified purge from every orifice before the muscles controlling their lungs fail, their chest tightens, and they eventually stop breathing altogether. Depending on the dose, death can occur within minutes.

  The grim and lethal effect of sarin gas on humans was known long before the Iraqi massacre brought this horrifying reality to the world stage. As early as the 1950s its reputation as the deadliest nerve agent made the USSR and America begin stockpiling it for military purposes. So in 1981 when a neuroscientist named William Summers proposed using a drug that also works by binding and paralysing acetylcholinesterase to treat Alzheimer’s patients, he trod carefully.

  Summers was interested in a drug called tacrine (otherwise known as 1,2,3,4-tetrahydroacridin-9-amine). Synthesised by an Australian chemist during the Second World War in a hunt to develop antiseptics for treating wounded infantry, tacrine was effectively shelved and forgotten to make way for penicillin. But animal tests using tacrine during the war effort revealed a curious property: it always counteracted the anaesthetic that scientists administered to an animal (usually a mouse) to put it to sleep. This intrigued another Australian, a psychiatrist named Sam Gershon, in the late 1950s. The arousing effect of tacrine appeared to stem from its ability to block acetylcholinesterase–making its behaviour similar to that of sarin gas but with a much less dangerous effect.