Superficially it makes sense. The brain is the main organ controlling how we cope with stressful experiences, and all stresses lead to some kind of change in neuronal circuitry. In the short term these changes are good: they promote resilience, personal growth and learning. In the long term, however, when a person is repeatedly exposed to stress, they lead to neuronal wear and tear. And I mean that literally: animal studies show that repeated stress exposure shrinks neuronal dendrites, strips synapses, and even stunts the brain’s ability to grow new neurons.1
Human brain imaging mirrors this sorry state. People with low social standing–that is, how a person ranks themselves within society–who report chronic stress have less grey matter in their prefrontal cortex.2 There’s even a report suggesting that three years after the 9/11 terrorist attacks, people who lived closer to the disaster had less grey matter in their hippocampus–the part of the brain that controls memory.3
Of course, the dimensions of human life are complex and multifarious. And the behavioural responses often associated with stress–diet, smoking, drinking, et cetera–make for a tangled web of cause and effect. That said, the evidence connecting stress to Alzheimer’s is growing, not fading. Indeed, veterans who suffer post-traumatic stress disorder (PTSD) are nearly twice as likely to succumb to dementia, mostly as a result of Alzheimer’s.4 And Alzheimer’s patients with higher levels of the stress hormone cortisol actually deteriorate faster.5
In the early 2000s a neuropsychologist named Robert S. Wilson at the Rush Alzheimer’s Disease Center in Chicago devised a study to explore the link further. Wilson interviewed over 6,000 elderly volunteers from south Chicago using what psychologists call the ‘neuroticism scale’, a test where people are asked to rate their level of agreement on a five-point scale: ‘strongly disagree’, ‘disagree’, ‘neutral’, ‘agree’, ‘strongly agree’. He then asked them to score a series of statements related to stress, such as, ‘I am not a worrier’, ‘I often feel tense and jittery’, ‘I often get angry at the way people treat me’, ‘I often feel helpless and want someone else to solve my problems’. At the same time, Wilson assessed the participants using a battery of cognitive and memory tests.
Three years later he repeated the test on the same volunteers (bar the small proportion who had died), and three years after that began fishing for statistical evidence linking stress proneness to Alzheimer’s risk.
The connection checked out. Of the 170 people who eventually developed Alzheimer’s, the vast majority scored highest on the neuroticism scale. The data suggested that a stress-prone person is 2.4 times more at risk.6 This finding was significant even after accounting for age, sex, race, education, medical history and possession of the APOE4 gene. When Wilson carried out another similar study a few years later, the result was the same, only the odds rose to 2.7 times higher risk.7 But how stress increases the risk of Alzheimer’s remains a mystery.
In an attempt to demystify the link, researchers at the University of California, Irvine, led by behaviour expert Frank LaFerla, took mice and concocted a method to stress them out in a human, ‘lifelike’ way. LaFerla argued that early attempts to understand stress in Alzheimer’s had failed because they’d looked at its effect over short time periods–minutes–or extremely long periods–days and weeks. This doesn’t really reflect the reality of stress for humans, he said. So his team sought to ‘mimic a short-term modern-life stressful experience, such as in car accidents and shooting events, which often last for hours rather than minutes or days/weeks’.8
LaFerla also pointed out that stress doesn’t just arise psychologically; it’s the result of physical trauma as well. He therefore wanted to stress the mice mentally and physically simultaneously. To do this, the mice were confined to small spaces and put on fast-moving platforms, all the while exposed to loud noise in a brightly lit room for five hours. Though these kinds of experiments do not sit well with me ethically, they have proved to be somewhat informative.
LaFerla’s researchers then looked in the animals’ brains. As expected, the mice’s dendrites and synapses had shrunk compared to non-stressed mice. Unexpectedly, however, the stress also raised beta-amyloid levels and caused severe memory impairments that lasted up to eight hours. Translating those findings to the human world, LaFerla’s team suggested that day-to-day stressful experiences–especially ones lasting several hours or more–might somehow accelerate Alzheimer’s or at the very least worsen the disease in its early stages.
Over half a century ago Hans Selye wrote:
Such expressions as, ‘This work gives me a headache’ or ‘drives me crazy’, grow out of experience… but there are imperceptible transitions [italics mine] between the healthy, the slightly disturbed, and the insane personality… it is often the stress of adjustments to life under difficult circumstances that causes a change from healthy to disturbed, or from disturbed to insane.9
No doubt his choice of words is outdated. But the idea, for mental health and now Alzheimer’s, perhaps resonates today more than ever: in our ceaseless endeavour to do and be more, we unconsciously integrate stress into the fabric of our everyday lives; we grant it acceptance and allow it to accrue; we forget that there are events in life where stress really is unavoidable (losing a job, getting a divorce, the death of a spouse). It’s critical, therefore, to recognise when stress is avoidable and do our best to control it–because Alzheimer’s is born of imperceptible transitions.
10
Diet
Let medicine be thy food and food be thy medicine.
Hippocrates
THAT PHRASE, WIDELY attributed to Hippocrates, has conjured up a host of novel nutrition fads, from the low-carbohydrate Atkins diet to the ‘caveman’ Palaeolithic diet, spawning an industry worth billions. They’re so popular, in fact, that the evidence for many of these diets has taken a backseat. We all know we should eat more fruit and fewer fats, more vitamins and less salt, but linking fixed diets to particular diseases is rocky terrain. Once again the problem lies in trying to prove causation based on observational studies. Nevertheless, there does appear to be some kind of relationship between Alzheimer’s and diet.
In early 2015 a group of researchers in Chicago, led by a neurologist named Neelum Aggarwal, published a report suggesting that a Mediterranean diet might prevent Alzheimer’s.1 Aggarwal and her team observed the diets of nearly 1,000 people aged between fifty-eight and ninety-eight over four and a half years. They found that those who followed a hybrid diet, i.e. a Mediterranean diet combined with one that lowers blood pressure, were 52 per cent less likely to develop Alzheimer’s. This included plentiful leafy vegetables, whole grains, fish, nuts and berries; minimal red meat, cheese, fried food, sweets and pastries.
Again, this is only an observation, but the link remained after factoring in the usual suspects: age, medical history, body mass index, education, depression and possession of the APOE4 gene. Moreover, a systematic review carried out at the prestigious Mayo Clinic in Minnesota concluded that ‘while the overall number of studies is small, pooled results suggest that a higher adherence to the MeDi [Mediterranean diet] is associated with a reduced risk of developing MCI [mild cognitive impairment] and AD [Alzheimer’s disease], and a reduced risk of progressing from MCI to AD’.2
How does what we eat protect us? It’s all due to a foggy connection between the brain and the gut. Collectively known as the microbiome, the bacteria that reside symbiotically inside us are vital to brain health. This was demonstrated most starkly in November 2014, when Swedish researchers at the Karolinska Institute in Stockholm showed that germ-free mice–gnotobiotic mice, housed and fed inside sterile containers–are born with leaky, defective blood–brain barriers.3 The blood–brain barrier is a wall of cells that decides what can and cannot enter the brain from the blood coursing through its capillaries. In Alzheimer’s, it’s one of the first things to break down, especially around the hippocampus, where memories are made.
But the microbiome can be a dangerous bedfe
llow too. If excessive amounts of bacteria breach the blood–brain barrier, they will activate the brain’s immune cells–microglia, the cellular protagonists of the Alzheimer’s vaccination story in chapter seven–and cause a form of inflammation that weakens the blood–brain barrier even more, setting in motion a vicious cycle in which more bacteria are let in and more inflammation ensues.
An irresistible case for this very scenario happening in Alzheimer’s was made six years ago by a Swiss-Hungarian neuropathologist named Judith Miklossy. She found that the density of bacteria is eight times higher in Alzheimer’s brains than in healthy people.4 Spirochaetes, the spiral-shaped variety of bacteria, were the main culprit. They have ‘the ability to invade the brain, persist in the brain and cause dementia’, Miklossy wrote. She also pointed out that dementia is a feature of late-stage Lyme disease, an infectious disease caused by the Borrelia bacterium. These micro-organisms can evade host defence mechanisms and ultimately help lead to the formation of plaques and tangles.
It turns out that the Mediterranean diet is filled with anti-bacterial foods–such as garlic, olive oil and honey. Cinnamon also weighs in, with one study demonstrating that cinnamon extracts fed to Alzheimer’s mice shrink plaques and improve cognition.5
Since writing this, a randomised clinical trial–the gold standard for assessing interventions, where participants are randomly assigned to either a treatment or placebo group to reduce bias–has been done on the role of diet in age-related cognitive decline (that’s not Alzheimer’s, of course, but experts agree this may apply nonetheless). Sweden’s Karolinska Institute was again leading the way. In what they dubbed the ‘Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability,’ or FINGER, scientists randomly assigned over 1,200 sixty- to seventy-seven-year-old Fins to a strict, two-year diet, and those who followed the diet did significantly better on cognitive tests than those who did not.6
As someone who obsesses over those colour-coded boxes divvying up food groups on food packaging, I loved the details of the study. The diet was as follows:
10–20% of daily energy from proteins, 25–35% daily energy from fat [less than 10% saturated fat, 10–20% mono-saturated fatty acids, 5–10% polyunsaturated fatty acids, and 2.5–3 grams per day of omega-3 fatty acids], 45–55% daily energy from carbohydrates [less than 10% from refined sugar], 25–35 grams per day of dietary fibre, less than 5 grams per day of salt, and less than 5% daily energy from alcohol.
In plain English: ‘These goals were achieved by recommendation of high consumption of fruit and vegetables, consumption of wholegrain cereal products and low-fat milk and meat products, limiting of sucrose intake to less than 50 grams per day, use of vegetable margarine and rapeseed oil instead of butter, and fish consumption at least two portions per week.’
Reading the study, I was almost disappointed. This advice has been a common narrative among doctors and dieticians for years. Now, however, we may have even more cause to listen.
11
Exercise
It is exercise alone that supports the spirits, and keeps the mind in vigour.
Cicero
FOR MANY, THE top seed in the race for lifestyle interventions is exercise. This is somewhat surprising considering the lack of hard evidence. But there’s an intuitive logic here that is somehow hard to dismiss. Suffice to say, the overall health benefits of physical activity are considerable. Even moderate exercise can markedly lower blood pressure and improve cardiovascular health. And it is these resulting rewards that are thought to directly affect Alzheimer’s risk.
Having high blood pressure in middle age, for instance, puts one at higher risk of Alzheimer’s.1 Conversely, if one’s blood pressure is too low, especially over the age of seventy-five, the chance of Alzheimer’s still increases.2 Why? That’s unclear. Most evidence points towards a link between blood pressure and inflammation (again involving microglia), but exactly how this feeds into the whirlwind of plaques, tangles and brain calamity remains an enigma.
What is conclusive, in lab mice at least, is that exercise on a treadmill can reduce the build-up of plaques and tangles.3 This modest miracle is thought to happen by activating an intriguing cellular phenomenon called autophagy (Greek for ‘eating of self’), a specialised kind of cellular housekeeping that clears out damaged or unwanted goods and introduces new ones after recycling the old, all as part of an adaptive and protective process to help neurons better cope with stress and extend their lifespan. So it’s thought that stimulating autophagy through exercise may halt the progression of brain cell death in Alzheimer’s.
To take the molecular parlance a step further, a protein called BDNF (brain-derived neurotrophic factor) is the leading actor in this subplot. In December 2010 researchers at the University of Pittsburgh, Pennsylvania, recruited 120 people with an average age of sixty-seven and had them perform either moderate aerobic exercise or simple stretches three days a week. Strikingly, follow-up MRI scans revealed that those who exercised netted a 2 per cent increase in the size of their hippocampus.4 That isn’t bad considering that 1.5 per cent shrinkage is normal for this age. And the middleman in this small victory, it appeared, was BDNF: a molecule known to promote the birth of new neurons and synapses throughout the entire nervous system. BDNF has such potent effects on neurons, moreover, that pharmaceutical companies now view it as a good drug candidate, causing some scientists to whimsically grant it the rather droll nickname ‘brain fertiliser’.
Such a wonder is, sad to say, perhaps decades away. So in the meantime we must resolve not only to exercise but also to learn what kind of exercise and how often it’s required to keep the mind fit. The most thorough investigation of the subject so far–a systematic review entitled ‘The effect of exercise interventions on cognitive outcome in Alzheimer’s disease’ by researchers at the University of Sussex, England, in 2014–could find several methods demonstrating positive effects on cognition in Alzheimer’s patients.5 They ranged from thirty minutes of walking (four times a week for twenty-four weeks), to one hour of cycling (three times a week for fifteen weeks), to thirty minutes of vigorous calisthenics (every day for twelve weeks). For those who have reached an age where even walking is a chore, gentle movements, such as those practised in the Chinese martial art Tai chi, were also deemed worthwhile.
The fact that both high- and low-intensity exercise appears to help speaks volumes. Larger studies are still needed to unequivocally prove a link with Alzheimer’s, and this certainly doesn’t mean that someone can avoid the malady simply by working out. This brand of science–epidemiology–dispenses truths about millions, not individuals. Indeed, my grandfather’s quotidian hike lasted two hours. But still, a little exercise is probably worth it.
Naji Tabet, chief author in the investigation and a lifestyle research front-runner, emphasised this point when I spoke with him on the telephone. ‘You do not have to run marathons. You do not have to go to the gym three or four times a week. A brisk walk will do!’ Tabet decided to focus on exercise as a way to prevent Alzheimer’s out of desperation more than anything else. ‘When you see an illness that robs someone of their personality, their individuality, an illness that ravages their life and the life of their loved ones, you have to treat it in whatever way you can.’
Tabet has looked at what fitness fanatics call Ultra Vets, people in their seventies or eighties who exercise religiously. (I’ve worked in a lab with someone who fits that description; he was eighty-two years old, had not retired, and had just trekked across the Antarctic.) When Tabet compared a group of Ultra Vets who had no memory problems with an age-matched group of people who do what you or I would say is a normal amount of exercise, he found no difference in cognitive skills between the groups. ‘So if you overdo it,’ he said, ‘there’s diminished returns. Just do low-intensity exercise. Keep the heart going, keep the muscles going, keep the respiratory system going. Even a couple of minutes a day might protect you.’
But still I wondered, how is th
is possible? ‘Nobody knows exactly how it works,’ Tabet granted. ‘My feeling is that exercise helps the immune system fight the build-up of plaques and tangles. But exercise also helps the mood. And we know that people who are depressed are more at risk of Alzheimer’s, so it might have an indirect effect by simply making somebody feel better.’
Fantastical though it might sound, Tabet also thinks that mild exercise can go a step further than prevention. He believes it may actually slow the decline of Alzheimer’s in late-stage patients. He insists that activities as simple as throwing a ball around, gently moving the arms and legs, stretching–anything, in other words, that meets his explicit and unadorned message to ‘keep things going’–will do something.
With that, remaining positive, I moved on to rediscover a different form of exercise altogether.
12
Brain Training
Anyone could be seduced by research when the results poured in. The trick was to love it when the results weren’t forthcoming, and the reasons why were elusive.
Lisa Genova, Still Alice
IN 2001 FORTY-ONE-YEAR-OLD Japanese physician Ryuta Kawashima began investigating the effects of video games on the brain. Based at Tohoku University in Japan after conducting neuroscience research at the Karolinska in Sweden, he already knew that functional brain imaging was his vocation; he found the hypnotic quality of seeing thoughts flash across a screen irresistible: here was a living map of the mind that responded to the observer like reflections in a mirror. Two years later, he published a book containing quirky cartoons of people performing daily activities next to miniature pictures of brains lighting up in response. He included straightforward mental arithmetic and various puzzles and quizzes–all, as the book clearly states, ‘to help you rejuvenate your brain and develop its functions to a higher level’. It was the author’s dream to make brain health maintenance ‘a social priority’. And in 2005 his dream manifested as a global sensation: the celebrated Nintendo Brain Training video game.
In Pursuit of Memory Page 12