In Pursuit of Memory

by Joseph Jebelli

  Collinge was flabbergasted. The government had spent more than £10 million specifically to develop technologies to detect and decontaminate prions, deadly pathogens that were so resilient they made viruses and bacteria look pathetic, and then ditched the entire enterprise as soon as it succeeded.

  Fellow experts were similarly nonplussed. Many gave testimony at the House of Commons session in support of Collinge. The blood test was ‘the next logical step’ said Marc Turner, director of the Scottish National Blood Transfusion Services. There was ‘a great deal of scope’ for these methods, echoed Roland Salmon, chair of the UK’s Advisory Committee on Dangerous Pathogens. Obviously, the next move ‘would be to conduct a study of the UK population using blood samples to understand what the frequency of prion infection in the blood actually is’, insisted Lorna Williamson, Research Director at the NHS Blood and Transfusion group.

  The report documenting this is a galling read.9 The Science and Technology Committee said the government’s behaviour was ‘unacceptable’, concluding: ‘We simply do not know, at present, how many people have been exposed to prions and what the implications of this might be… There is an urgent need to reduce this uncertainty.’

  Then Collinge’s Alzheimer’s paper came out. Wanting to avoid a public health scare, Collinge told the Department of Health about his findings before they were published. Again, he expressed his concern about the prion threat, and pointed out that many experts did indeed think that the eight CJD patients would have eventually got Alzheimer’s. This really wasn’t just about CJD any more.

  Instead of revisiting the issue, however, the same Chief Medical Officer set out to deride Collinge’s study. In a bizarre perversion of conduct, Davies took it upon herself to break the terms of Nature’s embargo and tell Richard Horton, editor of rival journal the Lancet, about the study. She asked Horton how he could help downplay the results. So the Lancet published an editorial slamming Collinge’s data.10 It was a strange move, seeing as Nature had already vetted the paper by peer review and Collinge had explained the study’s caveats. Then, Davies told the press: ‘I can assure people that the NHS has extremely stringent procedures in place to minimise infection risk from surgical equipment, and patients are very well protected.’11 Formally true, of course–just not when it came to prions.

  The Lancet’s main gripe was that the study hadn’t proven human transmission definitively, a critique Collinge vehemently contests. ‘Our paper doesn’t prove that it’s been transmitted this way,’ he explained. ‘It’s very hard to prove anything in biology, as you know. It’s rather like the arguments twenty years ago that asked, “Can you prove variant-CJD is caused by BSE?” Well, no one’s going to inject children with BSE and see whether they get CJD, but that’s how you would prove it. So it’s always going to be a collection of evidence. And you reach a point where it just seems so clear, and the weight of all this literature suggests that protein seeding is clearly an aspect of what’s going on in Alzheimer’s.’

  Although the headlines weren’t great–the Daily Mirror: YOU CAN CATCH ALZHEIMER’S; the Independent: ALZHEIMER’S MAY BE A TRANSMISSIBLE INFECTION–the articles themselves were good. Collinge had spent hours explaining his data to the press, and was pretty satisfied with the coverage. The Lancet’s editorial took more issue with his choice of words than the media’s. He had called the discovery a ‘paradigm shift’, when, according to them, it was ‘a long way from a true “paradigm shift”’.

  So was Kuhn’s accolade justified? ‘It’s a completely different way of thinking about a disease,’ Collinge emphasised. ‘We used to think of Alzheimer’s as this spontaneous, mysterious process that may be caused by genetic changes. But now, thinking of it as these protein seeds forming and spreading in the brain, which in certain circumstances can actually be transmitted by medical accidents…’ He paused and raised his eyebrows at me. ‘That’s a shift in thinking for most people.’

  Despite my ingrained scepticism, I found myself agreeing with him.

  The implications of the prion paradigm are far-reaching. A ‘transmissibility hypothesis’ of Alzheimer’s is forcing hospitals around the world to engage in an uncomfortable degree of self-scrutiny, and some have already begun to do so: scientists at the Center for Disease Control and Prevention (CDC) in Atlanta, Georgia, are now helping pathologists trawl through archives of post-mortem brain tissue to check for signs of amyloid seeds; the Pitié-Salpêtrière Hospital in Paris, France, is doing the same, as are several groups in Austria, Switzerland and Japan. While the evidence remains circumstantial–indeed, in March 2016 Pierluigi Nicotera of the German Centre for Neurodegenerative Diseases in Bonn told Nature’s Alison Abbott: ‘We have to remember that there is no conclusive evidence that seeds of amyloid can transmit actual disease or that amyloid spreads in the brain in a prion-like way’–others are not so sceptical. ‘In my opinion, all amyloids should be considered dangerous until proven safe,’ said Adriano Aguzzi of the University Hospital Zurich in Switzerland.12 I lean more towards the latter viewpoint by virtue of the oft-cited reasoning of astronomer Carl Sagan: absence of evidence is not evidence of absence. It will of course be years before we know the true extent of the role prions play in Alzheimer’s, but dismissing a disturbing hypothesis does nothing to help patients or the public appreciate the complexity of this seemingly ordinary disease. And by the mid-twenty-first century, when the need for treatment turns from necessity to urgency, we will need to have crossed every possibility off our list.

  17

  Looking but Not Seeing

  I felt totally alone, with the world receding away from me in every direction, and you could have used my anger to weld steel.

  Sir Terry Pratchett, Alzheimer’s Society, 2008

  THE DRIVE UP to Liverpool was becoming second nature to Pam and Richard Faulkner. From their rural home in south-western England, the route followed the M5 towards Birmingham, past the rolling hills of the Peak District, and on through Cheshire, before finally ending up in the hometown of Richard’s parents. It only took about two and a half hours. But during one such trip, on a January day in 2013, the couple found themselves approaching heavy traffic.

  Thinking on her feet, Pam pulled out a map. She’d learned how to navigate when she was a child, and often took on the role of map-reader during family excursions. They weren’t far from Liverpool. This would be a doddle, she thought.

  Staring at the map, however, she couldn’t quite believe what she was seeing. Or rather, what she wasn’t seeing. Everything looked muddled: the roads, the junctions, the symbols–none of it made any sense. She closed her eyes and then looked again… it was the same: completely unintelligible. Richard couldn’t understand what the problem was. Pam was only fifty-nine, hardly the age to be having such an odd mental lapse. But this wasn’t an everyday slip-up, Pam realised. It was something else. It was as if, in the blink of an eye, she’d forgotten how to read English.

  Flummoxed, Pam’s first recourse was to get new glasses (while Richard looked into buying a satnav). Though Pam had recently given up night driving–after the headlights from oncoming traffic frequently made her see a dizzying blue after-image–her optician couldn’t find anything particularly wrong with her sight. And so, at a loss, she simply put the incident behind her and went back to enjoying early retirement.

  A few months later, the problem returned. This time it was jigsaw puzzles and reading. Thousand-piece puzzles were Pam’s passion; anything less she deemed ‘wimpy’. But while deftly assembling her latest puzzle–an exotic Spanish garden–she suddenly noticed that she could no longer join the pieces together. The order was right; she just couldn’t physically align each piece. Similarly, newspaper columns became impossible to follow unless the text was justified on both sides. If not, she would reach the end of a line and then simply not know where to go next. And then, in June 2014, Pam found herself on the bathroom floor with no memory of how she got there. She’d had a seizure.

  At first the neurolog
ists struggled to provide an answer. Nearly all other aspects of Pam’s cognitive faculties were normal, as was an MRI of her brain. They diagnosed epilepsy but couldn’t explain why the seizures had started. Unsure exactly what they were dealing with, the neurologists prescribed anti-epileptic medication while a GP referred Pam to a memory clinic.

  But in a battery of memory tests Pam did surprisingly well. So the doctor pulled out a test she hadn’t performed since she was trained. It was a neuropsychological test of visual perception, depicting various objects at strange angles which are then rotated until the subject can accurately identify them. On this test, Pam was ‘bloody awful’, as she put it. On 15 July 2015 Pam finally got her true diagnosis. It was Alzheimer’s–but not as we know it.

  Visual Alzheimer’s, otherwise known as Posterior Cortical Atrophy (PCA), was first described in 1988 by the American neurologist Frank Benson.1 Unlike typical Alzheimer’s, people with PCA retain their memories, thinking skills and personal insight until much later in the disease. A patient with PCA, Benson wrote, is ‘aware of current events, and [shows] considerable insight into his or her predicament’. Instead, they experience a profound and surreal visual dementia. In addition to hallucinations, there are reports of people suddenly losing the ability to read, to accurately perceive movement and the size of objects, to recognise faces and find their way around familiar environments. There’s even a case of an individual who began seeing the world upside-down, in complete 180-degree reverse.

  The English fantasy novelist Terry Pratchett had this kind of Alzheimer’s, which he wryly called his ‘embuggerance’. In December 2007, upon learning his fate, Pratchett launched a relentless, seven-year campaign to put PCA in the public eye. Having published more than seventy books in a career spanning almost fifty years, he was furious that such an illness could strip the mind–and indeed the mind’s eye–so effortlessly. ‘I have the opposite of a superpower,’ he later wrote with trademark good humour. ‘Sometimes I cannot see what is there. I see the teacup with my eyes, but my brain refuses to send me the teacup message. It’s very Zen. First there is no teacup and then, because I know there is a teacup, the teacup will appear the next time I look.’2 Happily adopting the nickname ‘Mr Alzheimer’s’, Pratchett gave hundreds of interviews and made an award-winning documentary about his plight called Living with Alzheimer’s.

  It worked, too; nearly everyone I met for this book mentioned his name. During his final years, Pratchett travelled the globe in search of a cure, and was not averse to trying experimental therapies, including an ‘anti-dementia helmet’–thought, though certainly not proven, to treat Alzheimer’s by firing a burst of light into the skull to stimulate the growth of new brain cells. In 2014, one year before his death, he published a short volume titled Shaking Hands with Death, lucidly relating the feeling of PCA:

  Imagine that you’re in a very, very slow motion car crash. Nothing much seems to be happening. There’s an occasional little bang, a crunch, a screw pops out and spins across the dashboard as if we’re in Apollo 13. But the radio is still playing, the heater is on and it doesn’t seem all that bad, except for the certain knowledge that sooner or later you will be definitely going head first through the windscreen.

  That’s just one example. In his book The Mind’s Eye, neurologist Oliver Sacks described an instance of PCA in a pianist named Lilian Kallir, who could no longer read music and, when confronted by people’s faces, said, ‘It is not a blur, it’s a mush.’ So peculiar was her affliction that, in the months following their meeting, the pair became locked in a cat-and-mouse game for answers, with Sacks repeatedly showing her different pictures and shapes to elucidate the cause, and Lilian constantly thwarting his efforts with her baffling responses.3 He studied her in the familiar surroundings of her apartment in Manhattan, New York, where she organised her belongings based on size and shape, instead of meaning–like ‘an illiterate person might arrange the books in a library’, Sacks noted. Accompanying her on a trip to the supermarket, he noticed that her success was predicated on memorising the different blends of colour forming each aisle: colour, he said, was ‘her most immediately visible cue, recognisable when nothing else is’.

  Due to its strikingly diverse symptoms, PCA is thought to have gone undetected for decades, perhaps centuries. It’s still not known how many people have it, but some estimates put it at 5–10 per cent of all early-onset Alzheimer’s cases.4 To be clear, PCA isn’t a symptom of Alzheimer’s: it’s a different form of Alzheimer’s altogether. Many patients, including Pam, end up having unnecessary eye operations such as cataract surgery. Others, it’s thought, are simply never diagnosed. But there is nothing wrong with these people’s eyes. As an organ the eye only detects light from the outside world: after focusing on the retina, light is absorbed by a layer of photoreceptor cells and then sent inside the brain as electrical signals via the optic nerve. Vision itself is crafted deep within the circuitry of the brain.

  Look around you. Wherever you are, every aspect of the image you’re seeing–the assorted shapes, sizes, colours, depths, orientations and motions–are all generated by different networks of neurons in your brain. The seamless and movie-like projection we actually experience is a total illusion. Our world isn’t really ‘out there’ in the way we imagine; it’s compartmentalised internally, and then stitched together into a neuronal mosaic situated at the back of the brain, known as the visual cortex. Take me: I’m presently sitting in a departure lounge at Heathrow Airport. If just one part of my brain’s visual cortex shuts down, the people walking past me might suddenly appear to move in snapshots. If another fails, I wouldn’t know how wide to open my hands to grasp my cup of coffee.

  So it’s no surprise that plaques and tangles in the visual cortex spell disaster. And that’s exactly what happens in PCA. The pathology of Alzheimer’s starts there, and then spreads, years later, to the brain’s memory centres–the hippocampus and cortex. The cause is even more mysterious than classic Alzheimer’s. No genetic mutations have been confirmed, and the idea that APOE4 is somehow involved is heavily disputed. It eventually shrinks the brain in much the same way as Alzheimer’s. Patients are given the standard Alzheimer’s drug–an acetylcholinesterase inhibitor–because neurologists simply don’t know what else to do.

  But the riddle of PCA, I was about to learn, is beginning to unfold. And under close interrogation, it has some interesting things to say about typical Alzheimer’s.

  One of the researchers at the forefront of PCA is Sebastian Crutch at University College London. Convinced that visual Alzheimer’s holds important societal messages as well as biological intrigues, he decided to investigate using methods as unconventional as the illness itself. ‘It really is the same disease,’ Crutch said to me over the clatter of tourists when I met him for coffee at the London Science Museum. ‘It’s just in a different place.’

  Crutch hadn’t chosen to meet at the Science Museum on a nerdy impulse. He was here to tell the public about a project called ‘Seeing What They See’, a highly innovative attempt to enter the minds, so to speak, of PCA sufferers by building specific environments and then using motion-tracking sensors to see how they navigate. ‘The idea is that we can support their behaviour if we’re aware of what helps and what doesn’t,’ explained Crutch. ‘For example, we used some empty rooms–normal rooms: beige walls, wooden floors, lighting overhead–and measured how long it took for them to walk through one of three target doors which are illuminated by a moving cube. We’ve done experiments guiding them down corridors using different shapes, because Alzheimer’s isn’t just about disabilities; it’s about capabilities as well. And if we can understand what aspects of people’s vision are still functioning, we can use that sort of information.’

  According to Crutch, there’s a reason people with PCA preserve their memory for so long. On the one hand, he explained, there’s good evidence that genetic variants in the visual cortex cause Alzheimer’s to ransack this region first. But one can also arg
ue that these genes are actually protecting the brain’s memory centres by channelling the disease elsewhere, effectively cordoning memory off. That’s the viewpoint Crutch stands by. ‘If there’s something in PCA that actually protects your memory, something which means the disease isn’t pushing into the hippocampus to the same extent as in typical Alzheimer’s, I want to know about that.’

  Thirty-eight years old, with sleek dark hair and pale green eyes, Crutch comes from a family of engineers. His grandmother had Alzheimer’s, although his desire to do something about it appeared long before her mind fell. Throughout our conversation he animated every point with quick hand gestures and an intense stare. So eager was he to help me, in fact, he emailed me a study his team have yet to publish. It’s a rare delight to see the final draft of another group’s work before publication; many researchers are not so trusting. But the impression I got from Crutch was that he deemed this area of research too important to play politics.

  The study involved a crack team of forty-four scientists from seven different countries. They’d genotyped some 300 PCA patients and identified a host of new genetic risk factors. One of them, a gene dubbed SEMA3C, appears to corroborate Crutch’s hypothesis of memory-shielding genes in Alzheimer’s. In the visual cortex, SEMA3C aids the development of vision; but in the hippocampus, it supports learning and memory. It can do both because it’s thought to control ‘functional network connectivity’–that is, how the brain is wired to generate different cognitive processes. So when Alzheimer’s strikes, something about SEMA3C’s wide-ranging abilities might safeguard memory by redirecting the disease to the visual cortex. If Crutch can figure out what that ability is, he could theoretically design a drug that directs Alzheimer’s away from the hippocampus, and every other region of sacrosanct cognition, to some other place. Ideally, that place would be the brain’s glymphatic pathway, the system of glial cells and spinal fluid we saw in chapter thirteen, which clears the brain of waste products and is thought to underlie how the brain cleans itself during sleep. In this scenario, plaques and tangles would be the waste products, leaving improved cognition in their wake.