In Pursuit of Memory

by Joseph Jebelli

  PCA has thus revealed a weak link in the chain of Alzheimer’s, in that plaques and tangles may be far more mobile, and in turn more directable, than ever imagined.

  ‘All I could think was, how do we move forward?’ Pam said while I rested the Dictaphone on her living room table. It was a wet January afternoon in 2016 and I was talking to Pam and Richard at their English countryside home in a pint-sized village in Gloucestershire. ‘Because I didn’t want to cry, or hide in a corner and shake like a jelly. I just wanted to keep moving.’

  Pam is a bright, tech-savvy woman who grew up in South Yorkshire. As an only child, her parents doted on her–especially her father, a blasting engineer. So while the local norm in the 1970s was for young girls to find a suitable husband and stay at home, Pam decided to study physics at Oxford University instead. Working in the then burgeoning computer industry, she met Richard, a like-minded computer whizz whom she felt was more than suitable. The pair never had children, and have spent their days travelling, devouring books, enjoying the company of friends, and savouring English sunsets.

  ‘At the moment, it’s sort of okay,’ she explained with some hesitance. ‘I’m taking Aricept, which is definitely making me feel less fuzzy.’ As I continued to scribble everything the Dictaphone could not capture, I noticed that Richard made a point of giving Pam a white mug for her tea: the colour contrast is now a necessity. Bright or shiny objects don’t register with her, he explained. Even a teaspoon placed against their dark kitchen worktop may not be seen.

  Richard recalled one incident when they went trekking in Cornwall. It was a sunny day and the couple were traversing a coastal path that would take them down to the beach below when, suddenly, Pam froze. She could no longer see the path in front of her. The sunlight twinkling on the ocean had completely paralysed her gaze. ‘It was as if she couldn’t get her brain to move her eyes on to the path,’ said Richard, ‘so she grabbed my hand and we gently walked down together. That’s our normal practice now.’

  But the most tormenting loss for Pam is no longer being able to read. The proud owner of a library containing some 3,000 books, she’s not ready to convert to audiobooks. To demonstrate, she asked Richard to hand her a magazine and invited me to sit next to her. She began reading one of the columns aloud, but quickly stopped at the end of the first line.

  ‘Where do I go next?’ she asked me.

  I pointed to the line below.

  ‘Okay,’ she acknowledged, ‘but where’s the next line?’

  ‘This is the next line,’ I said.

  She sighed in exasperation. Despite seeing the same thing as I was, her brain refused to comprehend it.

  ‘But now it’s everything,’ she confessed. ‘I can’t pour drinks into glasses any more. I can’t chop an onion or do up shoelaces, because I can’t line anything up. In the garden I’d cut my fingers instead of the stems.

  ‘Pressure is also becoming a problem. I struggle with zips now because I don’t know how hard to pull. When I cut into food with a knife, I don’t know how hard to press.

  ‘What about soup?’ I asked.

  ‘No, eating soup I can’t do. Think about it: you have to take the spoon, pick some soup up in the spoon, hold it flat, and then get it into your mouth without pouring it down yourself. But I don’t know what’s flat.’

  A healthy brain performs these everyday tasks by activating a region called the posterior parietal cortex (PPC). This area is vital for planned movement and our apprehension of shapes. Activity in the PPC increases when subjects are asked to virtually navigate a familiar environment.5 The PPC is also thought to influence eye movements and how we grasp the location of objects in space.6 In Pam’s brain these functions are essentially scrambled because plaques and tangles disrupt the way electrical signals travel between nerve cells. As the functions of her PPC continue to fail, Pam’s symptoms will manifest in ever more strange and unexpected ways. (One patient Pam met can recognise her left and right shoe, but has no idea whether they are the same style and colour as each other.)

  Like Terry Pratchett, Richard and Pam decided to tell everyone about their baffling predicament. Richard made flyers titled WHAT’S GOT INTO PAM? and took them door-to-door. Under the subtitle WHAT CAN YOU DO? he wrote: ‘Treat Pam as you always have, but have patience with her when she is finding her way around and understand when her memory fails her.’ Like so many Alzheimer’s sufferers, Pam wants awareness, not sympathy; action, not sorrow. She and Richard regularly attend PCA support meetings and help out with Crutch’s ‘Seeing What They See’ project.

  It feels uncomfortable to say, but one of the benefits of this kind of Alzheimer’s is that the person retains a certain degree of insight. Pam’s world is slowly collapsing around her. She knows that what she’s experiencing is only a preview of what’s to come; that her memory will be next; that there will come a point when she can no longer find the bathroom in her own home. And yet, for the time being, she’s able to comment on her plight in a way most others cannot. Her Alzheimer’s can still ‘fit into a logical world’, as she elegantly put it, adding that ‘the wanting to know, to understand what’s happening, is still there.’

  People often mistakenly presume that there is one face to Alzheimer’s, but Pam has shown there is another. She’s a reminder of our endless duty to define and redefine Alzheimer’s, and a reminder that people’s experience of it is something no brain scan or blood test can ever communicate.

  18

  Between the Devil and the Deep Blue Sea

  The most fruitful basis for the discovery of a new drug is to start with an old drug.

  Sir James Black

  SIX HOURS WAS all it took. In a burst of potency and precision the drug found its target, locking on to receptors deep within the brain to jumpstart a molecular cascade. Like a pinball obeying the laws of motion, the impact ricocheted through neurons, reordering their inner ‘cogs’ and ‘springs’ until a new set of genes sprang into action. The mouse woke to the now familiar feelings of confusion and forgetfulness. But it felt better somehow–smarter. Of course, it would never know that a drug had just eviscerated a quarter of the amyloid in its plaque-riddled brain. Nor was it aware, three days later, that half of the amyloid would vanish. All it knew was that it had finally remembered how to ruffle tissue paper into a satisfying nest.

  The scientist watching couldn’t believe her luck, for this drug was already approved in humans. For the past thirteen years it had been used not for Alzheimer’s, but for skin cancer.

  In 2010, as the Alzheimer’s vaccination yielded unexpected insights, other researchers decided to do a little lateral thinking of their own. Among them were the American neuroscientist Tom Curran and the French biologist Yves Christen, who convened a meeting on 26 April in Paris. The topic under discussion was a remarkable tale of yin and yang: how Alzheimer’s and cancer are actually two sides of the same coin. The audience, having just started to dissect the biology of dementia, suddenly found themselves squaring an unexpected circle. How can cancer, the uncontrolled growth and proliferation of a single cell, be at all related to a disease characterised by countless cells simply withering away and dying?

  There was, no doubt, a connection. Statistics had shown that people who get Alzheimer’s have a lower risk of developing cancer.1 Inversely, if you develop cancer you’re less likely to get Alzheimer’s. The same holds true for cancer and Parkinson’s, and cancer and motor neuron disease. Genetic observations also spotlighted a link, in that cancer-affiliated genes–like p53 (mutated in half of all human cancers), ATM, CDK5, mTOR and PTEN (acronyms hauntingly familiar to many cancer victims)–all appeared to overlap with cellular pathways underlying Alzheimer’s.2 It was as if a pendulum was swinging between the two. Perhaps, then, slowing the arc towards one could slow the arc towards the other.

  From 8.30 a.m. to the close of the day, more than a dozen speakers tried to build a case for how this might be possible. Cancer is known to be an aberration of the cell’s normal life a
nd death mechanisms: mutated genes derail the cell cycle and lethal replication is the consequence. But neurons don’t divide, and so instead of impacting the cell cycle, neuronal damage appears to activate proteins that converge on the ‘death pathway’: a network of tightly controlled proteins that carefully dismantle the neuron from within. And this is where things get interesting, for many of those proteins are also involved in cancer. Maybe hitting Alzheimer’s with cancer drugs–drugs that work by essentially meddling with these protein networks–was therefore worth a shot. Maybe, as one French journalist wrote at the time, ‘this cross-fertilisation between the fields may well go on to bear a wonderful new crop’.3

  The first to reap such a harvest was neither a cancer biologist nor a qualified neuroscientist. A spunky twenty-two-year-old graduate student at Case Western Reserve University, in Cleveland, Ohio, Paige Cramer was a novice in the eyes of her mentors. And yet, on 23 March 2012, she submitted evidence to the pages of Science, arguably the most prestigious scientific journal, that a thirteen-year-old skin cancer drug called bexarotene could completely reverse the symptoms of Alzheimer’s in a matter of days.4 This was in mice, of course, not humans. But the effects were so profound that such a detail had–for once–taken a back seat.

  Originally from the emerald-green coast of Pensacola, Florida, Cramer grew up in a studious household. Her father is a physician and scientist, her mother an attorney in healthcare law. She told me that she remembers many evenings spent around the dinner table discussing diseases and puzzling scientific problems. She was almost custom-built for biomedical science, I thought. The scales were tipped during Cramer’s freshman year of college, when her best friend became paraplegic after a spinal cord injury, and Cramer decided that neurology needed more detectives.

  Brand-named Targretin®, bexarotene was designed to treat T-cell lymphoma–a rare type of skin cancer caused by white blood cells called T-cell lymphocytes–but it wasn’t very effective. Oncologists only prescribed it when patients didn’t respond to better medications. ‘Truth be told, I’d never heard of it,’ Cramer’s supervisor, Gary Landreth, told me. ‘It’s still controversial in the cancer business, because no one really knows how it’s supposed to work in T-cell lymphoma.’ So how was a cancer drug supposed to work in Alzheimer’s? I wondered.

  I kept digging. It turned out that what enticed Cramer was the drug’s ability to strike at the innermost chords of neuronal chemistry. Inside every cell, genes are activated by a special class of proteins called transcription factors. These proteins physically bind to DNA and then race along its threads like bows on a string. The result is a close copy of the gene, called RNA, which then rises up to ultimately do its job in the form of a protein. By boosting the activity of a transcription factor called RXR (retinoid X receptor) bexarotene thus acts as a kind of DNA conductor, directing the cell to prioritise certain ‘notes’, or proteins, over others.

  But Cramer’s attraction to RXR was something more than mere chemistry. Once active, RXR appears to control the levels of apolipoprotein E (APOE), the same molecule that won Allen Roses both fame and exile in the 1990s. Now here was a link worth exploring, Cramer thought. In the twenty years since Roses had pinpointed APOE4 as the prime genetic risk for Alzheimer’s, attitudes towards it remained mixed, and the trials targeting it had all run aground.

  But if one could truly modify APOE4, half of all Alzheimer’s cases might be history. And the upshot didn’t end there: good evidence suggests that APOE proteins help clear the brain of beta-amyloid. The details are typically fuzzy; for instance, it isn’t known whether APOE does this by physically latching on to beta-amyloid (like a Venus flytrap), or if it somehow recycles the plaques by other means. But in any event, the prospect of a tool capable of targeting two of the three main disease culprits was irresistible.

  And so, in an act as routine as it was startling, Cramer convinced a physician in her department to write her a prescription, and then wandered down to her local pharmacy to pick up the would-be Alzheimer’s cure. ‘It’s not really legal to do that,’ Cramer said to me over the phone, ‘but I was just a naive graduate student, one that was willing to try anything.’

  Upon returning to the lab, Cramer broke the cancer pills apart and began feeding them to her mice. Several hours later, the mice’s beta-amyloid levels dropped by 25 per cent. Within 72 hours the drop hit 50 per cent, an unprecedented result. She witnessed this in transgenic mice harbouring both Carol Jennings’s and Victoria Huntley’s genetic mutations, as well as mice engineered to display a particularly rapid and aggressive form of Alzheimer’s.

  By meticulously observing the mice’s behaviour over the next three days, Cramer also discovered that they were nesting just like they used to. Lab mice are usually given pieces of pressed cotton which they chew up and shred into nests. Transgenic Alzheimer’s mice lose the ability to do this, kind of like how human Alzheimer’s patients lose the ability to dress themselves, but Cramer’s mice were suddenly able to resume their nest-making.

  The mice that had been fed bexarotene also far exceeded their sick counterparts in maze trials and other tests of memory. One such test is known as contextual fear conditioning, in which a mouse receives a stimulus (usually a loud noise) followed by an unpleasant sensation (usually a mild foot shock), forcing it to adopt the stereotypical behavioural response of freezing like a statue. It’s somewhat cruel, I concede, but it’s highly informative. Of all the emotions, fear is perhaps the most closely connected to memory. Everyone remembers frightening experiences. It’s also an evolutionary imperative, and so organisms quickly learn what to be fearful of and respond in the same way at the mere sight of it. This was most disturbingly demonstrated in 1920 using a human child. ‘The Little Albert Experiment’, conducted by US psychologists John Watson and Rosalie Rayner, trained a nine-month-old baby to associate loud banging noises with the sight of a white rat. Thereafter, Albert became petrified when confronted by anything resembling a white rat–a white dog, a white coat, the white beard of a Santa Claus mask. The memory was seared indelibly on his mind.

  In the brain, fear conditioning is governed by an ancient interplay between the hippocampus and a neighbouring region called the amygdala. For Cramer, this gave the perfect opportunity to see how deep bexarotene’s effects on memory really went, because a good fear response is predicated on a healthy hippocampus. ‘Think about the idea as you hear a train,’ she explained. ‘Generally speaking, if you’re near a train track you’ll look both ways, because you have that association of moving-train-equals-danger; be careful. Someone whose memory hasn’t developed properly, or whose memory is impaired, won’t make that connection and will continue to walk near a track without looking.’ That Cramer’s demented mice could again be fear conditioned, therefore, indicated a powerful resurgence in neuronal connectivity.

  That wasn’t all. In considering how else she could assess their memory, Cramer decided to focus on smell. It may surprise you to learn that one of the first things many Alzheimer’s patients experience is ‘anosmia’, the partial or near total loss of smell. What shouldn’t surprise you is that memory and smell are intimately linked. I for one, at the faintest whiff of a familiar scent, am instantly flooded with images and feelings of past events; even memories I’d long forgotten come crashing back. It’s due to the way smell is wired in the brain, being processed by a region called the olfactory bulb. And like the amygdala, the olfactory bulb sits right next to the hippocampus.

  Interestingly, Alzheimer’s patients appear to have an especially hard time smelling peanut butter. A 2013 study performed by Jennifer Stamps, a researcher in the Department of Food Science and Human Nutrition at the University of Florida, instructed a group of patients to close their eyes and identify the smell from a container holding 14 grams (a tablespoon) of the condiment.5 When the patients struggled to detect the scent, Stamps moved the container 1 centimetre closer to their nostrils. She found that Alzheimer’s patients required the peanut butter to be about 10 ce
ntimetres closer than both healthy people and patients with other types of dementia. The anosmia was largely confined to the left nostril, which is thought to be because Alzheimer’s damages the left side of the brain more than the right. The relationship between smell and Alzheimer’s is now so well documented that scientists are trying to use smell as a biomarker for early diagnosis.

  By measuring the electrical activity of a circuit within the olfactory bulb, known as the piriform cortex (from the Latin pyriformis, meaning ‘pear-shaped’), Cramer found that her transgenic animals’ sense of smell was being enhanced by drug treatment. ‘This is really exciting,’ she noted, with audible exhilaration, ‘because it’s another benefit for neuronal networks, for the strengthening of connections between brain regions.’

  Landreth echoed her excitement. ‘In mice it’s like magic. The effect of this drug is so rapid in reversing the pathology. Think about this: bexarotene is the first example of a drug that actually modifies Alzheimer’s disease mechanisms. And it works in thirty days.’

  I myself remember the buzz surrounding this discovery. I penned a piece for Pi, University College London’s student newspaper, calling attention to it (much to my supervisor’s chagrin; I could have been doing more experiments instead). Listening to Cramer and Landreth retell the story, something about it still stirred me. It all started with a doctor handing her a prescription and telling her to head to a drug store. Was the elusive cure for Alzheimer’s sitting on a shelf in our pharmacies all along?