In Pursuit of Memory

by Joseph Jebelli

  He is an astute neurobiologist and a brilliant geneticist, but is one of the few people to stress how little we know about memory. ‘We haven’t the faintest idea how the brain generates memory. We don’t even have a useful definition of memory. And you’re going to write a book about a disease that assaults this function, but you cannot even define it! What the hell are you doing?’ Again, he had a point. I’d become so wrapped up in trying to understand Alzheimer’s that I’d swept the basic premise of what memory is under the rug.

  ‘What about LTP and the synaptic network idea?’ I countered. Wasn’t this at least somewhere in the ballpark?

  ‘What can I say?’ he acknowledged with a shrug of ambivalence. ‘It sounds reasonable. But my God is it magical.’

  One of Stefánsson’s trademark characteristics is his ability to view disease at the population level. Where many see a cruel and utterly meaningless defeat, Stefánsson sees the tragic but inevitable cost of evolution.

  Take schizophrenia: in March 2015 DeCODE used the DNA of 86,000 Icelanders–plus a further 35,000 people from the Netherlands and Sweden–to show that schizophrenia and creativity actually share genetic roots.4 The same genes underlying the disorder, it turns out, are also more common in painters, dancers, writers and musicians. So it isn’t that you develop schizophrenia and therefore think differently, Stefánsson explained; it’s much more likely that you think differently and therefore develop schizophrenia. Since the prevalence of schizophrenia is only 1 per cent worldwide, people with these genes have a roughly 10 per cent chance of developing the disorder. And this, he claims, is the small but striking price our species pays for the Mozarts, Shakespeares and Van Goghs of society.

  A similar paradigm may exist for Alzheimer’s owing to another special property of the Icelandic mutation: it protects against memory loss and cognitive decline in normal ageing, too. By using a cognitive test given to residents of Icelandic nursing homes, DeCODE found that people who carry the mutation are nearly eight times more likely to reach eighty-five as mentally sharp as they were at their peak. For Stefánsson, this is irrefutable proof that Alzheimer’s is simply an accelerated form of ageing. ‘What’s often lost on people is that the brain is just an organ. And like everything else it’s perishable. I mean, you look at yourself in the mirror in the morning and you see over the years that you change: your skin changes, your hair changes, your muscles change. Your brain changes as well. It deteriorates.

  ‘I think Alzheimer’s is somehow an expression of this fact. I mean, is it a design flaw when a disease terminates a life when we are relatively old, or is it a masterpiece in the design? That depends on how you look at it. It depends on whether you look at it from the point of view of the individual, or the point of view of the species.’

  ‘Assuming that’s true, what evolutionary bill is Alzheimer’s footing?’ I asked. ‘Or is that the wrong question?’

  ‘This is exactly the right question,’ Stefánsson replied. ‘We’re born to have offspring and die. What our roles are beyond that is beyond me. I don’t know why we last this long. But there is some data to indicate that the Grandmother Effect is real.’

  The Grandmother Effect is a fascinating theory. Formulated by anthropologists in the late 1990s, it argues that the reason grandmothers live many years after menopause is to help daughters with childcare. It was the Hadza hunter-gatherer tribe in Tanzania who first lent credence to the idea; researchers found that mothers in the tribe have more children if their own mothers helped raise them. (Grandfathers, by contrast, can stay fertile until they die and so the explanation for their longevity is that it’s either for them to continue mating, or that it’s some kind of genetic side effect of female longevity.)

  It goes without saying that child-rearing demands grandmothers be mentally sound, certainly Alzheimer’s-free, and today evolutionary biologists are uncovering genes responsible for exactly that. One such gene, CD33, was found in our closest relative, the chimpanzee. Intriguingly, though, this gene only grants mind-protective status when it’s found in humans. And since chimps and other primates usually die once their fertility ends, it’s possible that genes like this have evolved solely in humans to make the Grandmother Effect a reality. As the distinguished Indian physician Ajit Varki told a journalist in 2015: ‘Grandmothers are so important, we’ve even evolved genes to protect their minds.’5

  Still, Stefánsson is no fatalist about ageing and Alzheimer’s. Even if ageing is ‘paid for’ by Alzheimer’s, we have still evolved minds to eradicate the illness. Before getting to the knotty issue of treatment, however, I wanted to know what he thought about the influence of stress, diet, education and sleep–the topics still fresh in my mind.

  He took a dim view. ‘I think there’s no solid evidence for any of these. There have to be environmental factors for Alzheimer’s, and whether it proceeds slowly or fast, but I honestly don’t know what they are.’

  It wasn’t the answer I wanted to hear. Then again, much of what I’d learned was an answer I didn’t want to hear; it was almost becoming a sign of the truth. In any case, lifestyle measures were a low-hanging fruit. Iceland’s real gift was the message it sent to the pharmaceutical industry.

  Around the time Big Pharma was testing amyloid immunisation in clinical trials, vast swathes of neuroscientists were devising a back-up plan. What if, they thought, instead of trying to rid the brain of amyloid, we prevented it from ever arising in the first place–like in the brains of Icelanders with the mutation?

  Since the discovery that amyloid was merely the by-product of a normal protein–the amyloid precursor protein, APP–questions were asked about what the APP protein was actually doing in the brain. Beyond sitting at a neuron’s surface, with one end jutting inside the cell and the other out, no one really knew. Perhaps it was just another run-of-the-mill signalling molecule, a ‘sedan’ on the grand intercellular highway of brain chemistry. Whatever its purpose, it certainly had a routine: first an enzyme chopped off a large piece of it, which then allowed a second, smaller piece to be released from the neuron. Although I should say unleashed, for this small piece was beta-amyloid, the substance of plaques.

  In 1999 five independent groups of scientists identified this chopping enzyme. They called it BACE (beta-site APP-cleaving enzyme).6 It turned out that Carol Jennings’s genetic mutation caused BACE to ramp up its activity, which had the effect of churning out beta-amyloid much faster than normal. It was akin to a faulty traffic light stuck on green–and too many sedans were getting through. So scientists looked into the possibility of blocking BACE and redressing the balance.

  The results were not encouraging. From 2003 to 2011 a tide of animal tests unveiled serious side effects. Mice genetically engineered to lack the enzyme suffered blindness, seizures, spine abnormalities and memory problems to boot. Switching BACE off was clearly not ideal. What about chemically restraining it? In 2011 E-Lilly was among the first to try this tack. The ‘BACE-inhibitor compounds’, as they became known, were certainly better, but blindness remained a vexing fly in the ointment.

  Still, progress of a kind.

  So Lilly kept at it, tweaking and retweaking the recipe until the animals finally appeared normal. Compound LY2886721 was the coveted batch. It produced no side effects and yet, crucially, reduced beta-amyloid formation in the animals’ brains. A success! The company immediately moved to human trials. Upon giving forty-seven healthy volunteers daily doses of the drug for a fortnight, everything looked fine. Emboldened, Lilly funded a six-month Phase two trial in 130 cases of mild Alzheimer’s.

  Here, you guessed it, is where things went wrong. An undisclosed number of patients showed signs of liver damage. Not wanting to take any chances, Lilly immediately terminated the trial. Merck, another US pharmaceutical company, picked up the baton. Their drug, dubbed MK-8931, made it through eighty-eight healthy volunteers with no side effects. And so they cautiously pressed on. Despite Merck’s headway, however, the message in the pharmaceutical industry was
clear: invest elsewhere.

  One could hardly blame them. Between 2000 and 2012, of the 244 Alzheimer’s drugs tested in 413 clinical trials, only one was approved (NamendaTM, a drug similar to the acetylcholinesterase inhibitors, and similarly insufficient). In total, the drug candidates racked up a lamentable 99.6 per cent failure rate–even higher than cancer, at 81 per cent.7 Our unsophisticated grasp of the disease, combined with the dizzying cost of drug development–it costs about $100 million per trial; over $2 billion all-in–made Alzheimer’s drugs, in the words of one pharmaceutical chemist, ‘almost perfectly set up for expensive failures’.8 The reluctance for renewed attempts almost seemed a fait accompli.

  But then something magical happened. Further detective work at DeCODE revealed that the Icelanders’ protective gene caused their BACE enzyme to reduce its activity. In other words, the mutation was a natural BACE inhibitor. If that wasn’t proof this lead was worth pursuing, nothing was.

  Wide-eyed and reinvigorated, Big Pharma returned to the table. And to share the risk, they teamed up: Lilly joined forces with AstraZeneca, the British–Swedish pharmaceutical giant, pledging a whopping $500 million to co-develop a new BACE inhibitor; Eisai, the Japanese company, struck a deal with the US company Biogen; and Swiss-led Novartis partnered with Amgen. The abundance of heavyweight competition marked a momentous victory for Alzheimer’s research.

  Hungry for a release date, I rang every company.

  ‘We’re talking somewhere between five and ten years,’ said Sasha Kamb, Amgen’s Vice-President of Discovery Research. ‘DeCODE has proved that this idea should work, so I think the only question left is: when do we need to intervene and by how much?’

  Ricardo Dolmetsch, Global Head of Neuroscience at Novartis, was even more optimistic. ‘Between three and eight years. I think Kari Stefánsson’s data provided the nail in the coffin that beta-amyloid is important and that if you inhibit BACE that would be a good thing.’

  The most cautious estimate I got during these prying exchanges was from a representative for Eisai. ‘Seven to twelve years,’ she had said, not exactly bursting the bubble.

  As to whether they will work, I kept something Stefánsson had told me fresh in my mind. ‘They’re going to be spectacular,’ he’d said.

  Driving through the barren lava fields of the Reykjavík peninsula, en route to the airport, I mulled over Stefánsson’s special role in the abolition of Alzheimer’s. No doubt he was another William Summers, another outlier, only one with the formidable power of genetics on his side. When his contribution would actually help people like my grandfather, Arnold, Carol, Marie, Victoria, Li and Pam, I couldn’t say. Big Pharma’s projections seemed ambitious, but I vowed to remain optimistic.

  Looking out of the window, at the flat expanse of all-consuming darkness, I suddenly glimpsed the fleeting glow of a streetlight puncturing the polar night. For a brief moment I could see the snow was melting.

  Spring was coming.

  20

  Insights from India

  Where the mind is without fear and the head is held high,

  Where knowledge is free,

  Where the world has not been broken up into fragments

  By narrow domestic walls,

  Where words come out from the depth of truth,

  Where tireless striving stretches its arms towards perfection,

  Where the clear stream of reason has not lost its way

  Into the dreary desert sand of dead habit,

  Where the mind is led forward by thee

  Into ever-widening thought and action,

  Into that heaven of freedom, my Father, let my country awake.

  Rabindranath Tagore, Gitanjali, 1912

  THE WHITE-ROBED MAN hands me a cup of chai while the midday sun pelts his calloused fingers. This is Hari Chand, a farmer in the village of Shahpur Kalan, in Ballabgarh, northern India. His ninety-four years of age asserts his status as village elder. And he’s not alone: nearby, several more elders stoop on wooden benches to smoke the customary hookah pipe, quietly chatting while offering me looks of curious bemusement.

  Ballabgarh is a patchwork of twenty-eight villages located some thirty-five kilometres south of New Delhi. Its elderly inhabitants are mostly illiterate, impoverished farmers, many of whom have never left the village. I’m here to retrace the steps of a sixteen-year investigation, which started in 1988, when the US National Institute on Aging set out to widen the net for Alzheimer’s clues:

  Other countries, cultures, ethnic or population groups, with different exposures and habits, may offer clues to the [cause] of the disease that are not apparent in Western industrialized nations. The need to search more aggressively and widely for potent modifiable risk factors requires movement beyond national boundaries.1

  Looking around, I’m hard-pressed to think of a more suitable candidate for such an objective. Many of the villagers are bone thin; clearly malnourished. They live in crumbling sugar-cube houses or wooden shacks covered with corrugated metal sheets. They burn cow dung for fuel. Electricity is a luxury few possess. And water is supplied by a single cement basin and a few rusty pumps. But another difference seemed to be their resistance to dementia. Sporadic reports from New Delhi’s Centre for Ageing Research suggested that Alzheimer’s was ‘unusual’ in this part of India, that plaque and tangle pathology were ‘rarely found’ post-mortem.

  ‘My memory is good,’ Chand said proudly. ‘I think there are some people in Ballabgarh who don’t want to remember certain things, but I’ve never heard of anyone having problems with their memory.’ Chand has farmed these fields since he was ten years old. His memory stretches as far back as his teenage years, to the arguments his mother and father had when they had to borrow money to pay the British colonialists’ high taxes. Having retired at the age of eighty-five, Chand now spends his days in the company of his ten children, eight grandchildren and seven great-grandchildren. After reeling off all their names for me, he said that I’m not the first scientist to visit his town. Others had come with similar questions, not so long ago.

  Leading the NIA study was Mary Ganguli, an Indian-born psychiatrist at the University of Pittsburgh, Pennsylvania (in collaboration with Vijay Chandra and colleagues at the Centre for Ageing Research and the Department of Community Medicine of the All India Institute of Medical Sciences). She had her work cut out. The study required a group of elderly people in a region where many don’t know their real age, family histories in a community where medical records are virtually non-existent, and cognitive tests in an area where few have ever put pen to paper or kept track of the Roman or Hindu calendar. It moved us from the realm of telephones and bank accounts to the era of spirits and storytelling around the fire. It was, at heart, a radical act of learning by unlearning, advancing by retreating.

  ‘They have the same cognitive functions as educated people,’ Ganguli explained over the phone. ‘It’s just about finding a reasonable way to tap them. It’s important because we might have learned all we’re going to learn, or most of what we’re going to learn, by only studying the risk factors for dementia among white people in wealthy countries.’

  To overcome the cultural and educational disparity, Ganguli’s team devised ‘culture-fair’ tests of cognition. Since the villagers speak a phonetic dialect of Hindi, for example, they were asked to repeat certain sounds instead of reading or writing things down. Questions involving abstract mental arithmetic, like the subtracting seven task I did in chapter four, were personalised to questions about rupees and village bus fares. As an adaptation of the standard task ‘Write a sentence’, the researchers instead asked participants ‘Tell me something’–anything to gauge their ability to generate a complete thought.

  A bewildered ‘What shall I tell you?’ was a common response, often leading, Ganguli wrote, to ‘awkward and pointless exchanges between interviewer and subject’. The experience resulted in the final version being ‘Tell me something about your house.’ Even the idea of taking a test w
as alien to many of them. When asked to memorise a list of words, most villagers simply laughed and asked, ‘What for?’ When told a story and asked to repeat it, many would say, ‘You call that a story? Let me tell you a story!’ before proceeding to embellish the original tale with great dramatic flair. When the interviewers insisted they follow the rules, they often replied, with sincere wonder, ‘Why?’

  At one point the team tried something called the Boston Naming Test, a neuropsychological exam where the candidate is shown line drawings of various objects–a boat, a whistle, a kangaroo–and asked to name them. But the objects were completely unfamiliar to the villagers. Some even had difficulty with the concept of a drawing, and started grasping at the paper itself for more insight. So Ganguli decided to use 3-D models instead. One was a miniature model tree, which a member of her team had purchased in a children’s museum back in Pittsburgh. To avoid confusion, he’d cut the wooden base off before posting it to Ganguli.

  ‘Okay, what’s this?’ she asked when she presented it to them.

  ‘Broccoli,’ came the reply.

  A different approach was clearly needed, and so she decided to focus on her subjects’ ability to perform normal day-to-day business. Not too much is expected of these elderly citizens–cooking, working the fields and tending the fire are all done by younger family members. Daughters-in-law are especially required to look after them. ‘At a certain age, many of the women hand over the pantry keys to their eldest daughter,’ Ganguli explained, ‘and then sit back and relax. They become ladies of leisure, if they can afford it, if there are enough daughters to do all the work.’