In Pursuit of Memory

by Joseph Jebelli

  I’ve never been much good at Kawashima’s famous game. I was somewhat surprised to hear it’s been touted as a way to prevent Alzheimer’s–I didn’t think people took it seriously in health, let alone disease. But believe it or not, for over a decade it has been used in thousands of nursing homes across Japan in a desperate attempt to do precisely that.

  A mere glance at some demographics explains why. The East Asian island nation is now home to the fastest ageing population on the planet. Nearly a third of its citizens are above the age of sixty-five, and this is set to climb to 40 per cent by 2055.1 Combine that with the estimated drop in Japan’s population from 127 million to 90 million in the same timespan–due to notoriously low birth rates–and it’s not surprising that the country is on the brink of a dementia epidemic. The dire situation has led the Japanese minister of health to call for a million extra foreign nurses and carers by 2025, to thwart a population collapse.

  So, does it work? Kawashima certainly thinks so. ‘I believe that the brain is a brain, whether it’s in children or older people.’ Kawashima was sitting opposite me in his office at Tohoku University in the northern Japanese city of Sendai. I’d become too fascinated by the idea of a computer game treating Alzheimer’s to miss the opportunity of a face-to-face meeting with him. ‘I know that naturally the brain deteriorates during the course of ageing, but I think that we can maintain a certain level of cognitive function using Brain Training.’

  ‘Even with Alzheimer’s?’ I asked.

  ‘Sure!’ Kawashima replied, almost surprised by the question. He told me that more than 30,000 people are using Brain Training, and that the effect in nursing homes is dramatic. ‘People frequently ask me to visit their nursing home, in fact. They say they are seeing unbelievable changes. I didn’t believe it at first; I thought, they tell me a lie. But then I went and it was true. Patients who were doing nothing before, just sleeping and sitting in a wheelchair, were doing simple arithmetic problems.’

  I couldn’t help but be struck by Kawashima himself. He was immaculately dressed in a long black suit and looked twenty years younger than his fifty-six years of age. He has a calm, gentle manner, which I soon realised betrayed a supreme underlying confidence. Despite the scepticism surrounding his invention–not to mention being branded a charlatan by some of his peers–he seemed somehow above it all. He wasn’t trying to cure Alzheimer’s. He was simply trying something new and wildly innovative; something that just might buy patients a little extra time.

  Perhaps the most striking observation, though, was the fact that his bookshelves were filled in equal measure with books and Nintendo DS games. He pulled one down to show me. ‘This is Nintendo Concentration Training. It is very hard. In Japan it’s called devilish training.’ He pointed to a picture on the cover. It was a picture of the familiar animated floating head of Kawashima. ‘Look, here is my face as a devil!’ he exclaimed, laughing.

  ‘This is too hard for people with dementia, of course, but now I am interested in the prevention of dementia. And as you know, the beta-amyloid and tau proteins are already accumulating in the brain from age forty to fifty, so I believe we must all do brain training regularly before age forty.’

  Before meeting Kawashima, I’d done some digging into the scientific veracity of cognitive training. Some researchers believe that any positive effects are due to something called the Hawthorne, or observer, effect, in which people change their behaviour when they know they’re being observed, internally vocalising particular tasks, for instance, that might improve their score but don’t reflect any underlying improvement in cognition. Others argue that the brain remains modifiable throughout life, and that we simply haven’t developed the right tools to see how everyday experiences can affect it.

  In September 2009 the Alzheimer’s Society funded a huge trial involving more than 13,000 people. They found that while cognitive training did nothing for people under the age of fifty, it did help those over sixty with everyday tasks such as shopping, memorising lists and overseeing finances–provided they play it for ten minutes, five times a week for six months.2 Improvements like these can last for up to five years, some researchers say. In more visceral terms, cognitive training has actually been shown to improve blood flow to the prefrontal cortex–a region so integral to human thought it’s been called the ‘organ of civilisation’–and strengthen nerve connections between brain hemispheres in seventy-year-olds.3

  On whether it’s an Alzheimer’s deterrent, the simple answer is: we still don’t know. A few reports suggest it might work. In 2012, for instance, a US group spent five years investigating 700 people over sixty-five and found that those who frequently did crosswords and puzzles, or played cards and checkers, were 47 per cent less likely to develop Alzheimer’s.4 But the study was bedevilled by its modest size, leaving many unconvinced.

  Consider this by cognitive neuropsychologist André Aleman, who wrote in 2014: ‘Cognitive training is nothing more than practising mental capacities such as memory, concentration, and thinking skills… [and] is often extremely specific, while the decline is across the board. So if you do a lot of Sudoko puzzles, you become extremely good at Sudoko puzzles, but your brain hasn’t necessarily become sharper in other areas.’5

  But while emphasising that the research behind Brain Training is still in its early days, Kawashima left the door open to the immensely powerful effect he believes the game has on the brain. ‘We know that the prefrontal cortex is activated by brain training,’ he said, ‘and the prefrontal cortex plays many roles in higher cognitive functions–like memory, attention and decision-making. So if we can stimulate the prefrontal cortex in one way, then basic functions of the prefrontal cortex must improve. That’s my hypothesis.’

  It sounded reasonable enough to me–certainly enough to make me want to pick up my old console and devote some time to it before I turn forty. Here in Japan, the Mecca of the video-gaming world, I realised that this game is not just an entertaining gimmick: it’s a purposeful and evolving technology. Indeed, Kawashima is trying to dissect its neurological effects using an experiment he calls neurofeedback, wherein a person can see their brain activity on a computer screen while playing the game, and has to concentrate on trying to control certain patterns of activity by focusing more or less on different aspects of the game. Unsurprisingly, Nintendo continue to watch Kawashima’s research closely.

  Kawashima is certainly no snake oil salesman, though. He turned down a 15 million pay cheque for his invention, and still refuses to keep any of the $30 million amassed in royalties.

  ‘My wife is not happy with that,’ he told me, grinning.

  ‘Why didn’t you keep any of it?’ I asked in disbelief.

  He shrugged. ‘I didn’t feel it belonged to me. I just did my job as staff at the university. And my salary is paid for in taxes by the Japanese people, so I felt it belonged to the university.’

  Kawashima has channelled the game’s profits into research at Japan’s Tohoku University, where he now leads a group of forty young neuroscientists. Two of them–Susumu and Akira–offered to show me around the lab. In a starched white room inside a building opposite Kawashima’s office, they were testing Brain Training on mice. Well, not quite. But the experiment they’ve set up is a pretty neat simulation. First the mice live in bare, empty cages, with hardly anything to stimulate their brains. Then they’re moved to an ‘enriched’ cage, containing toys, tunnels, multiple floors and a maze which Akira changes three times a week to outfox them. Using a specialised mini-MRI machine, Akira then has a look at their brains. ‘I’m looking for signs of plasticity,’ he told me, ‘changes in the structure and connectivity of the brain.’ Astonishingly, every time Akira trains his mice using the enriched environment, their brains get bigger. And here’s the crucial point: this happens with both old mice and transgenic Alzheimer’s mice.

  Akira thinks it might have something to do with another relevant theory called brain reserve. Conceived by an American geriatric resear
cher named James Mortimer, the idea is that each person’s brain holds a certain amount of resistance to mental decline, irrespective of how much structural damage has actually occurred. Mortimer believed brain reserve is intrinsically linked to the amount of mental stimulation a person engages in throughout life: the greater the stimulation, the greater the brain reserve. He was convinced it was the reason people could have plaques in their brains without ever experiencing dementia.

  In 1990 Mortimer teamed up with epidemiologist David Snowdon to study brain reserve in a group of highly educated centenarian nuns at the convent of the School Sisters of Notre Dame in Mankato, Minnesota. Snowdon believed nuns were perfect candidates for such a study. Their uniform living arrangements and exceedingly regular diet and exercise regimes helped rule out conflicting variables, allowing a more focused look at the role of education. The sisters’ fastidious record-keeping also meant he had access to medical and historical records dating back to the late 1800s. Among these records were collections of autobiographical essays that the nuns had written as part of their inauguration to the convent, when they were in their early twenties. By analysing the essays’ grammatical and linguistic sophistication–what Snowdon called ‘idea density’–he discovered a strong connection with Alzheimer’s.

  For example, a sister describing her siblings was more likely to get Alzheimer’s if her essay read like this: ‘There are ten children in the family six boys and four girls. Two of the boys are dead.’ As opposed to a sister whose essay read like this: ‘Already two, a brother and a sister, had begun the family which would gradually reach the number of eight… When I was in the fourth grade death visited our family taking one to whom I was very particularly attached, my little brother, Karl, who was but a year and a half old.’

  An incredible 90 per cent of the sisters with low idea density went on to develop Alzheimer’s, and from these essays alone–essays written some sixty years earlier–Snowdon could predict with 80 per cent accuracy which sisters would do so.

  The amazing findings of the ‘Nun Study’, as it became known, prompted a wave of media interest. One nun even appeared on the cover of Time magazine behind the catchline: BELIEVE IT OR NOT, THIS 91-YEAR-OLD NUN CAN HELP YOU BEAT ALZHEIMER’S. As Snowdon wrote in Aging with Grace:

  We now know that the brain is capable of changing and growing throughout life, but there is no question that most of its growth comes during our earliest years… Parents ask me if they should play Mozart to their babies, or buy them expensive teaching toys, or prohibit television, or get them started early on the computer. I give them the same simple answer… ‘Read to your children.’ 6

  Brain reserve, if real, is a developmental phenomenon. But what it offers is lifelong neuroprotection.

  For Kawashima, though, flexing the mind in adulthood is far from too late. And with Japan’s booming Alzheimer’s epidemic, his mission is now more urgent than ever. ‘My future is to succeed with prevention,’ he said as I bade him goodbye. ‘That’s my hope… My dream.’

  13

  Sleep

  Sleep is a rose, as the Persians say.

  Vladimir Nabokov, Lolita

  NO ONE KNOWS why we sleep. The obvious answer is that we do it because we’re tired. But the brain is 95 per cent as active during sleep as during our waking hours. And that, given our evolutionary legacy as prey for larger predators, not to mention the amount of time we lose for reproduction and food gathering, makes the reason for sleep all the more mysterious.

  For decades there have been theories to better explain it, ranging from wound healing and heat regulation, to memory consolidation and dream-induced creative thinking. But recent work, published in leading scientific journals, suggests that sleep may also exist to shield the brain from Alzheimer’s.

  It began in 2005, when a group of psychiatrists at St James Hospital in Dublin demonstrated a link between sleep disturbances, like increased insomnia and daytime sleeping, and the severity of dementia in their Alzheimer’s patients.1 This didn’t come as a surprise–many brain disorders correlate with sleep disturbances–and so it was mainly viewed as practical knowledge to help doctors and caregivers choose the right medicine to help their patients sleep.

  But others believed the link was more far-reaching; that something deeper was at play. So scientists set about replicating the paradigm in Alzheimer’s mice.

  Among them was a group at Washington University, St Louis, led by a man named David Holtzman. His team showed that beta-amyloid levels fluctuate with sleep–wake cycles: depriving mice of sleep raises beta-amyloid levels, while chemically stimulating sleep lowers them.2 That was 2009, and the discovery was soon supported by the group’s converse observation, in 2012, that vaccinating the mice against beta-amyloid restored normal sleeping patterns.3

  One year later, Maiken Nedergaard and her team at the University of Rochester, New York, found evidence that the brain actually cleans itself during sleep,4 removing beta-amyloid using a network of microscopic channels filled with spinal fluid called the glymphatic pathway: a kind of plumbing system composed of glial cells that clears the brain of waste products. She compared the sleeping brain to a ‘dishwasher’ clearing out molecular ‘dirt’. The findings were impressive. The only nagging caveat was that mice (besides being mice) are nocturnal; they have different sleeping behaviours to us. A human study was desperately needed.

  This came from researchers at the University of California, Berkeley, led by a neuroscientist called Matthew Walker. For Walker, a young, fresh-faced, jocular professor originally from England, sleep is more intimately tied to memory than people realise. He likes to preface his lectures by assuring people that they are allowed to fall asleep during his talk. ‘Knowing what I know about the relationship between sleep and memory,’ he recently told one audience, ‘it’s actually the greatest form of flattery, for me, to see people like you not being able to resist the urge to strengthen what I’m telling you by falling asleep.’5

  In July 2015 Walker and his team recruited twenty-six healthy people with an average age of seventy-five, and set out to uncover the relationship between sleep, beta-amyloid and memory.6 To begin, Walker performed PiB-PET scans on the recruits to gauge their brain’s amyloid quota. Then he made the participants memorise sets of word pairs before asking them to spend the night in a sleep laboratory, where their sleeping patterns could be professionally monitored.

  Sleep moves in roughly ninety-minute cycles, made up of rapid eye movement (REM) and non-rapid eye movement (NREM) phases. REM sleep only lasts around ten minutes and happens while dreaming (though why the eyes move is unknown). Deep and dreamless NREM sleep dominates each cycle, but becomes less dominant later in the night as REM sleep encroaches slightly more into its time. Memory consolidation is thought to occur during an NREM phase called slow-wave sleep–a period of synchronised, low-frequency pulses of electrical activity. This is what Walker was particularly interested in for the human study.

  The next morning, Walker’s recruits retook the word-pair test during a functional MRI brain scan. As it turned out, the participants with the highest beta-amyloid levels had the lowest slow-wave activity and scored the worst on memory recall. The reduced slow-wave activity was most prominent in the prefrontal cortex–the brain region where beta-amyloid accumulation was at its highest. This was seen after correcting for age, sex and brain size. What’s more, the participants were told to abstain from stimulants such as coffee and alcohol two days before testing. Mathematically, there is a linear relationship by which beta-amyloid affects sleep, which then affects memory. This makes sleep itself a possible candidate for therapeutic intervention in Alzheimer’s. Walker published the study in Nature Neuroscience and, predictably, received full-bore sensationalism from the press.

  But there are two problems with the study. First, the findings are correlative: they don’t prove cause and effect. For that, people’s sleeping habits would have to be followed over several years. Second, it’s possible the results were sway
ed by the recruits’ having to sleep in a new environment. Walker had asked them to make home sleep logs and told them they could sleep in the laboratory in the same way, but without somehow measuring the difference between the two settings, the findings remain open to interpretation.

  Which is precisely what Holtzman and fellow neurologist Brendan Lucey have done. ‘Despite these issues,’ they wrote in an opinion article accompanying the study, ‘the study by [Walker’s team] provides important new insights into the changes in sleep and memory in preclinical Alzheimer’s disease, as well as indicating potential new avenues for investigation.’7 They’ve argued for alternative ways that the trifecta of beta-amyloid, sleep and memory are connected. According to them, it may be that beta-amyloid affects sleep and memory simultaneously, or that sleep problems associated with ageing affect memory and beta-amyloid, which in turn affects sleep, creating a self-perpetuating loop of havoc. How tangles fit into this is unknown. But hurdles aside, few would dispute the importance of a good night’s sleep, and this blossoming new area of research wholly and irrefutably strengthens that mandate.

  What are we to make of so much ambivalence? If my grandfather were alive today, he’d probably tell you to live like a rock star; the austere life he led certainly didn’t protect him. But still, there’s no denying that the evidence for non-pharmacological countermeasures against Alzheimer’s, albeit conflicting, exists. Of course, as a scientist, I’d be the first to say that evidence alone isn’t enough–it has to be good evidence: large samples, widely replicated, and so forth–but since we know that these lifestyle measures are good for us anyway, the most sensible approach is to play it safe. So follow a Mediterranean diet. Exercise. Avoid stress. Stimulate your mind. Sleep. You’ve got nothing to lose and everything to gain.