In Pursuit of Memory Read online

  So, let’s play out Roses’ hypothesis. Over time, a brain starved of energy causes the functions of its neurons to decay, and like a city undergoing economic collapse, its service sector, or proteins, will start to malfunction–hence both the plaques and the tangles–until eventually the neuron gives up and self-destructs. But unlike other cell types, neurons can’t replace themselves. So with each loss the energy burden on neighbouring neurons increases. And as an organ that constitutes 2 per cent of the body’s weight yet requires 25 per cent of its energy, this is bad news for the brain. Unable to cope, more neurons self-destruct, a pathological cascade is initiated, and Alzheimer’s takes hold.

  For the goal of treating Alzheimer’s effectively, both theories had their merits and pitfalls. Hardy’s theory drew a straight line between amyloid and the disease, offering pharmaceutical tycoons an easy target. But it also imposed a narrative that was arguably too simplistic. And as ‘seductive as this narrative might be,’ one critic recently wrote, ‘the dementing illness that we recognise as Alzheimer’s disease is associated with a complex biology and biochemistry, as well as a pattern of brain disintegration that cannot easily be explained by a simple linear disease model.’9

  Holding APOE4 responsible, on the other hand, would help plumb the genetic depths of old-age dementia, and perhaps help explain why amyloid formed plaques in the first place. But a gene that merely increased the chances of disease left drug discovery empty-handed. As one pharmaceutical magnate told me, ‘Yes, APOE4 is by far the most prominent genetic link. But it doesn’t mean anything. You can’t offer someone who is APOE4-positive any therapy.’10

  But there’s a third option: what if neither theory could explain the disorder?

  The fundamental precept of good science is that there is no place for beliefs. It’s why scientists are repeatedly taught to replace ‘believe’ with ‘think’. Enter our third group: the Tauists.

  Tau stands for ‘tubulin-associated unit’. It’s the name of the protein that forms Alzheimer’s tangles, the twisted knots of debris that seem to strangle neurons from within (the ‘paired helical filaments’ that Kidd and Terry spent years arguing about). Discovered in 1986 by three separate groups of researchers, tau normally acts as a kind of sealant for ropelike structures called microtubules, which stretch out along axons to create an internal transport system for every neuron. Scientists discovered that tau becomes tangled when it mixes with too much phosphorus inside the neuron. This tangled, hyperphosphorylated tau causes microtubules to fall apart. And that fact led the Tauists to assert their own hypothesis on the cause of Alzheimer’s, which has come to be called, fittingly, the tau hypothesis.

  Picture a zip-line whizzing sacks of crops between high-altitude villages in the tropics (farmers actually do this in Bolivia and other parts of South America). If the line comes apart, the crops won’t reach their destination. For the neuron, those crops are neuro-transmitters and biochemical nutrients, whizzing along the axon en route to synapses and other neurons. The failed deliveries have lethal consequences. Millions of synapses, the wellsprings of memory, will collapse and vanish. Then the axon itself begins to deteriorate, dying back until nothing but a limbless cell body remains. With all lines of transport and communication effectively terminated, internal chaos ensues and cell death becomes inevitable. When the neuron finally dies, all that’s left are eerie coils of tau–what neuropathologists call ‘ghost tangles’.

  For Tauists, then, Hardy and Roses are both wrong. What’s more, they have misunderstood the nature of Alzheimer’s. There is no ‘primary event’ in the disease. Amyloid and APOE4 are just two triggers and there are probably many more. The crucial point was this: whatever triggered the disease, it all converged on a common end point–tau. It represented the ‘how’ behind neuronal death, when all else only represented the ‘why’. It was, in short, all that truly mattered.

  The idea had hefty support. Alois Alzheimer himself would have been more Tauist than Baptist. In 1911 he wrote: ‘We have to conclude that the plaques are not the cause of [old-age] dementia but only an accompanying feature.’11 And by the mid-1990s it had emerged that there are more than twenty brain diseases caused solely by tau malfunction–known collectively as tauopathies. If that wasn’t enough to give tau the respect it deserved, argued the Tauists, nothing was.

  At scientific conferences at the time the debate was raging. But the Baptists stood their ground. ‘Tangles aren’t particularly important,’ Hardy told the New York Times’s Gina Kolata in 1995. He remains convinced that tangles are merely the result of plaques and therefore less worthy of our attention. It is inescapable that we should wonder how all this infighting actually helped patients. But such quarrels were and still are compulsory, because there are many theoretical paths for developing an effective drug. If we ceased thrashing out the best possible path, then the solution might take even longer to arrive.

  I myself lean towards the amyloid cascade hypothesis, for the simple reason that amyloid appears to be where Alzheimer’s begins. But I also think it unwise to assume that this fact somehow diminishes the relevance of APOE4 and tau tangles, because our understanding of causation remains unsophisticated. We still don’t know, for instance, whether biological causes produce their effects by guaranteeing them: the inescapable fact that many people develop plaques yet remain cognitively healthy exemplifies that point. Thus, the cause of Alzheimer’s is unlikely to be one single thing.

  The most conspicuous flaw in the Tauists’ argument was a lack of genetic evidence. Unlike amyloid, no mutations in tau were found in Alzheimer’s patients, and without genetics as a guiding light, the idea of building a case against tau was like telling detectives to find a murderer by asking random people on the street. It was a messy lead, in other words. And at the start of a new century, the Baptists kept the upper hand, while the Tauists fast became renegades.

  Meanwhile, steadily ticking over in the background, the world’s largest, most ambitious biology project was under way: the Human Genome Project. Initiated in 1990 by the US Congress, the goal was to map every gene that made up a human being. Costing $3 billion and involving scientists in some twenty different countries, it was the biggest collaboration of biologists the world has ever seen.

  On 14 April 2003, when the final draft was unveiled, it was heralded as the most valuable information humanity has ever known: ‘More significant than splitting the atom or going to the moon,’ declared Francis Collins, the project’s US lead scientist; ‘The most wondrous map ever produced by human kind,’ announced US President Bill Clinton; ‘The foundation of biology for decades, centuries or millennia to come,’ said the UK lead John Sulston, who was to win a Nobel Prize for his work.

  For Alzheimer’s research it was game-changing. As the technology improved, thousands of patients rallied to have their genome sequenced, giving rise to genome-wide association studies (GWAS), in which small, previously hidden genetic variants could be uncovered. To date, more than twenty genetic variants have been identified–and the list will grow.

  7

  The Second Brain

  Man is not made for defeat.

  Ernest Hemingway, The Old Man and The Sea

  THEY HAVE BEEN called many things–‘spider cells’, ‘little bags of poison’, the ‘other brain’1–but they are officially known as glia. Alois Alzheimer himself knew about glia; under the microscope they looked like scars bordering plaques and dead neurons. But like other scientists of his generation, he considered them little more than structural filler, and so for nearly a century they were overlooked. About thirty years ago, however, when scientists realised that glia constitute over half the human brain, they decided to take a closer look.

  There are three types of glia.

  Astrocytes: Greek for ‘star cells’ due to their shape, astrocytes are the largest, most numerous type. They control brain functions by mediating how neurons ‘talk’ to one another. In the hippocampus, for example, a single astrocyte contacts up to 140,0
00 neuronal synapses. In The Other Brain, astrocyte expert Douglas Fields argues that this behaviour is more complex than neurotransmission, meaning that higher mental faculties like consciousness, thoughts and feelings may actually be governed by astrocytes. They divide and die like other cells, and can grow uncontrollably in the most lethal type of brain cancer–glioblastoma.

  Oligodendrocytes: Greek for ‘few branched cells’, they are the cellular factories of myelin, a fatty substance that insulates neurons by wrapping around their axons like the plastic sheath of copper wire. Myelin is white, hence the term ‘white matter’ as opposed to ‘grey matter’, referring to neurons themselves. A human’s need for oligodendrocytes is darkly illustrated by multiple sclerosis, the devastating and common neurological condition caused by the widespread destruction of myelin. Without myelin, nerve impulses are disrupted, leading to fatigue, muscle weakness, visual problems and cognitive dysfunction.

  And then there’s microglia, literally ‘small glia’, the third and most important type for our story; these are the brain’s immune cells. Swarms of these comparatively tiny cells orbit neurons in a surveillance state, constantly scanning them for signs of distress using long, antennae-like projections. In this mode they’re dubbed ‘resting’ microglia. Once a threat is found, however, they transform from guard to soldier-at-arms. These ‘activated’ microglia then unload a payload of toxic chemicals to rid the brain of unwelcome guests such as meningitis and malaria.

  This is important because in the late 1980s post-mortems revealed that Alzheimer plaques were often completely surrounded by microglia.2 At the time no one quite knew what to make of this. But by 2001 advances in neuroimaging had made it possible to see activated microglia in living brains. In healthy people, the images nearly always showed a dim glow of activity across the brain. In Alzheimer’s patients, though, the brain was lit up like a Christmas tree.

  At face value it looked like a classic immune response–as if the microglia were attacking the plaques in a bid to eliminate them from the brain. The idea that the immune system could be involved in this way had radical and conflicting implications. On the one hand it suggested the brain was trying to remedy the problem from within; that we had, in effect, an ally on the inside. From this came the idea that perhaps the microglia just needed a helping hand, and that by artificially ramping up their healing power, the brain’s immune system could be harnessed to treat Alzheimer’s.

  But this rose-tinted outlook was counterbalanced by something far less optimistic. Mounting evidence from cell culture research showed that microglia also appeared to kill neurons if their activation wasn’t controlled.3 I’ve done this experiment myself: leave microglia in a dish with neurons and a low dose of immune stimulant–fragments of bacteria or dead cells, for instance–and they will eventually turn on their neuronal neighbours.4 Through the microscope the neurons look like a satellite image of a city at night, with the lights getting dimmer as clusters of circular bodies slowly blot them out.

  This fact was once the bane of my existence. For two years I tested whether an experimental drug could hold off the microglia and allow the neurons to flourish. Every morning, including weekends, I entered the university, slipped on a white lab coat and blue rubber gloves, doused myself in sterilising ethanol, and had a look at how my cells were doing. What came next was usually the sight of dead neurons, an abrupt expletive (the standard response of a young scientist) and a phone call to cancel whatever social obligation I had planned. Others continue to work on the drug, but it’s still unclear why the microglia do this to the neurons–whether the response is deliberate or just collateral damage.

  In any case, the evidence suggested that the internal chaos of plaques and tangles might cause microglia to become dangerously overactive. These sabotaging cells could then start a deadly, self-perpetuating cycle of toxic inflammation, besieging the brain and driving the disease into a downward spiral. If that was the case, scientists had to wonder: would powering down the immune system help Alzheimer’s patients?

  Both scenarios were theoretical, of course, and arguably too simplistic. Microglia might be both good and bad for the brain. The answer depended on several unknowns, such as what state they were in when the disease started, how long they had been activated, and the role of genetic and environmental influences. But there was, unfortunately, precedent for the darker alternative. And two other types of dementia exemplify that point.

  The first is neuroAIDS. In 1983, one year after the US Center for Disease Control and Prevention established the term AIDS to describe the opportunistic infection affecting young homosexual males, it was noticed that some AIDS patients also developed nervous system abnormalities similar to those seen in Alzheimer’s. After experiencing a severe decline in memory, concentration, attention and language, they would end up bedbound and incontinent, usually dying three to six months later. It was often the earliest and sometimes only indication of a patient suffering from HIV. By 1987 researchers introduced the term ‘AIDS dementia complex’ to highlight the virus’s impact on cognition, but it is now most commonly referred to simply as neuroAIDS. Although the anti-retroviral therapies released in the 1990s did appear to ameliorate neuroAIDS symptoms for some patients, exactly what combination of drugs was best suited for the purpose remained unclear. Today it’s estimated that 10–25 per cent of HIV-infected patients develop this kind of dementia.5

  But from a purely scientific standpoint neuroAIDS provides a powerful lens for pinpointing what brain changes are perpetuating the symptoms of Alzheimer’s. NeuroAIDS is a disease with a known primary cause–a virus–and this gives scientists an opportune place to anchor their thoughts, because viruses are fixed entities in space and time and abide within well-defined parameters. Exploring this, scientists soon learned that after entering the brain the first cell type the HIV virus infects is microglia; neurons are spared until much later in the disease. That suggests that microglia, not neurons, are the core perpetrators of the symptoms of dementia.

  Another form of dementia that gives a clue is called Nasu-Hakola, named after the Japanese pathologist and Finnish physician who first reported it in the early 1970s. This condition remains puzzling to this day. A patient with Nasu-Hakola first experiences severe bone fractures, usually during adolescence, in their hands, feet and knees. This can persist despite bone transplantation. Bizarrely, the young patient then develops a slowly progressing dementia, involving memory loss, personality changes, indifference and apathy towards those around them, problems with speech, and disorientation. Again, strikingly similar to Alzheimer’s. By the mid-1980s researchers spotted that most cases were either of Japanese or Finnish descent, suggesting a genetic cause. And by 2000 geneticists had zeroed in on two culprit DNA mutations in the genes DAP12 and TREM2, both of which code for receptors on–you guessed it–microglia.

  Suddenly microglia were in the spotlight. Experiments focusing on what their normal functions were and how mutations affected them were devised. Comparisons between Nasu-Hakola microglia and microglia in Alzheimer’s were drawn. Therapeutic strategies to rein in their suspected overzealous behaviour were discussed. Scientists still weren’t sure if they were allies or saboteurs; many ominously called them the brain’s Jekyll and Hyde.

  So when Dale Schenk, at a new company in San Francisco called Athena Neurosciences, wanted to empower microglia for an immune-based therapy on Alzheimer’s patients, it was, to say the least, a bold move.

  ‘I just had a simple idea,’ Schenk told me over the sound of stirring teaspoons and soft chatter. Scientists don’t usually meet under golden chandeliers and marble columns, but I’d managed to catch fifty-eight-year-old Schenk at a biotechnology conference being held at New York’s illustrious Waldorf Astoria Hotel. His ‘simple idea’ was one so innovative that many scientists admitted they would never have thought of it. A vaccine for Alzheimer’s.

  We normally associate the term ‘vaccine’ with viruses and bacteria. Outbreaks of bird flu, Ebola and now Z
ika saturate the press with stories about the race to invent vaccines. But in pure biological terms, vaccines are any kind of agent that stimulates an organism to develop immunity. They can be dead or weakened forms of the threat itself–like Jonas Salk’s polio vaccine and GlaxoSmithKline’s chickenpox vaccine–or antibodies: blood cell proteins that label pathogens for destruction.

  Schenk’s vaccine for Alzheimer’s was called AN-1792, and it consisted of synthetic beta-amyloid. His aim was to trick the brain into thinking that the plaques themselves were the foreign invaders, and thus stimulate a potent immune response. ‘I thought, if we vaccinate mice with beta-amyloid,’ he said, adjusting his glasses, ‘they’re going to develop antibodies to beta-amyloid and have them circulating in their blood, right? And a small fraction of those antibodies are going to get into the brain. Over time, that should disrupt beta-amyloid and dissolve the plaques.’ Schenk grew up in Pasadena, California. The son of a fire chief and newspaper columnist, he went into science because ‘it just seemed like a good idea’. After his PhD he worked on heart disease for a company called California Biotech. Then, one day in the mid-1990s, tired and frankly bored of the heart, he got talking to a colleague working on John Hardy’s amyloid hypothesis.

  ‘So what does beta-amyloid actually do?’ Schenk remembered asking him.

  ‘Oh, I don’t know,’ said his colleague.

  ‘What do you mean you don’t know?’ urged Schenk.

  ‘No one knows what it does, they just think it might cause Alzheimer’s.’

  ‘Well that’s stupid. All it does is stick together. How could it cause Alzheimer’s?’

  The conversation continued in this vein until Schenk, finally convinced by the hypothesis, decided to join his colleague at Athena Neurosciences, where Schenk has now worked for the past twenty-eight years.