But these weather-beaten seniors do have some responsibilities, like watching over grandchildren, and overseeing festivals and marriages; so the team devised a new scoring system based on questions such as, ‘Does he express his opinion on important family matters?’, ‘Is she able to remember important festivals such as Holi, Diwali?’, ‘Does he ever lose his way in the village?’ The results confirmed what many had already declared. There was a curiously low level of Alzheimer’s in the village.
It was the BBC that first alerted me to this story. In February 2010 it ran an article headlined INDIAN VILLAGE MAY HOLD KEY TO BEATING DEMENTIA, in which the remarkably wholesome lifestyle of Ballabgarh’s residents was pointed to as the reason for their low rates. ‘The people of Ballabgarh are unusually healthy,’ it announced. ‘It is a farming community, so most of them are very physically active and most eat a low-fat vegetarian diet. Obesity is virtually unheard of. Life in this fertile farming community is also low in stress, and family support is still strong, unlike in other, more urban parts of India.’
But Ganguli told a different story. Despite all the effort that had gone into carefully developing the assessment tools, her instinct was that something was off–that an elusive, protective agent, somehow camouflaged amid the vicissitudes of Ballabgarhian life, was wishful thinking. There were too many ‘what ifs’; too few absolutes. The villagers’ diet, for instance, consists mainly of whole-wheat flatbreads, lentils, vegetables and yoghurt. Since everyone in the village eats this, whether it makes any difference is impossible to say. The idea of a stress-free life in Ballabgarh also seems fanciful. The villagers’ livelihood hinges on a capricious climate, with drought and crop failures giving Indian farming a notoriously high suicide rate. Indeed, during my visit, Chand explained how the Indian government is further assaulting their livelihood by buying the farmland cheap and urbanising it for foreign investors. Only by increasing their yield can they hope to survive as an industry–and so every day, said Chand, they pray, nerve-racked, that ‘the gods give the rain’.
To this day Ganguli has mulled over what else it could be. Whether or not physical activity protects them is another unknown, not assessed by the study–though Ganguli lends more credence to this possibility than any other. ‘It’s quite possible. They’re an active community. They walk everywhere. They don’t have cars. When they were younger many of them worked the fields, which is hard physical labour, so that might be protective.’ Chand told me he spent ten to twelve hours a day ploughing the fields; sometimes his family even slept in the fields. ‘And we know that everything that’s good for the heart is good for the brain. The trouble is–and I’m sure you’ve come across this–Alzheimer’s pathology begins in our brain when we are much younger, decades before symptoms start. So we would need to perform a trial where we make half the younger villagers follow the same exercise protocol for the next forty or fifty years to see if it really reduces their risk.’
Genetics might play a role. Ganguli’s team genotyped more than 4,000 villagers–aged fifty-five to ninety-five–and found that the APOE4 gene is rare here compared to more developed parts of the world. But even this explanation had pitfalls: APOE4 increases the risk of heart disease as well; did the APOE4 carriers die of heart disease before they could get symptoms of Alzheimer’s? Which begged another question. Was this all just a function of India’s low life expectancy, which according to the latest average is sixty-two?
To understand the answer, it’s important to know the difference between disease prevalence and disease incidence. Prevalence is the proportion of people at any given time with the condition: a kind of snapshot of a population. Incidence is the rate at which new cases of disease occur in the population over a defined period of time: one year, for instance. The relationship between incidence and prevalence is duration, and for Alzheimer’s, it’s duration of survival. Two populations might therefore have the same incidence of Alzheimer’s but prevalence would be higher in the population that lives longer.
In the west, we maintain elderly people in good health, meaning they can live a long time with dementia. In India and other developing nations, however, cultural influences can preclude this kind of sustained healthcare. The children often keep their parents at home, do all the housework, feed them, wash them and nurse them if they get sick. As Chand’s eldest son explained to me, ‘From when we first start walking, from the very first time our parents hold our hand, it is our duty to look after them. When they get old, they need our hand, our support–no matter how sick they become. This is our culture.’ Rather than being a product of low life expectancy, then, it’s possible that underreporting, due to the low expectations of Ballabgarh’s elders and the unparalleled level of respect and care they receive from the young, may have concealed many cases of Alzheimer’s from Ganguli’s study.
I liked the way Ganguli viewed this riddle. It reminded me of something I’d almost forgotten. Science is messy, its tools forever incomplete. In the lab we’re largely cocooned from this. Everything comes neatly packaged in IKEA-style kits. If something doesn’t work, it’s usually the fault of the scientist. And when a tool isn’t up to the challenge, we often just wait for one that is. We push boundaries from the comfort of clearly defined lines. But Ganguli and her team scrapped all that. They were going back to basics, back to the styles of Joseph Priestley and Alfred Russel Wallace–intrepid explorers, poking in the dark for the eurekas only this approach can dispense.
She mentioned a similar study, carried out in 1995, in which researchers compared Alzheimer’s prevalence between African Americans living in Indianapolis and Nigerian Africans in the city of Ibadan, Nigeria.2 The contrast was powerful for essentially neutralising genetic differences–the African Americans had migrated to America during the slave trade 200 years earlier, which is arguably not enough time for intermarriages to outweigh environmental influences. Lo and behold, Alzheimer’s prevalence was lower in Nigeria than in Indianapolis. Again, nobody really knows why. Evidently something in the environment is at play.
Another report, published a few years earlier by the same group, supports that suspicion. They looked at a population of Cree Indians in Winnipeg, Manitoba.3 It may be Canada, but the native Cree live in sovereign reservations with a culture and tradition all of their own. Most of the men continue to hunt and fish well into old age. Many of the women maintain an interest in elaborate crafts like sculpting and quillwork. They still embrace modern society (the buffalo-hide tipis are just for show) and yet the prevalence of Alzheimer’s remains unusually low. If an undiscovered guardian is somewhere in their environment, the most ‘striking impression’, the report noted, was the ‘continuity of activities of the elderly Native subjects’. Keep active, in other words. Stay busy.
The rejection of cultural differences has consequences, too. A 1996 study published by the National Institute on Aging, entitled ‘Prevalence of dementia in older Japanese-American men in Hawaii’, found that elderly Japanese people living in America have higher rates of Alzheimer’s than those living in Japan.4 Nearly 4,000 participants aged seventy-one to ninety-three were involved, impressive even by today’s standards. Though the cause of the discrepancy was never determined, researchers largely attribute it to the western diet–especially because Alzheimer’s rates in Japan have shot up since the gradual westernisation of the country’s diet. ‘Genetics loads the gun, lifestyle pulls the trigger’ is a popular biology adage. It reconciles the argument over nature versus nurture, and each of these studies is a stark reminder of it.
Before I left Ballabgarh, I saw another group of elders sitting in a circle beneath a wooden shelter. They were playing card games, laughing merrily while their children worked in the acres of paddy fields around them. In spite of so much uncertainty, it definitely seemed that they were doing something right.
While the search for that ‘something’ continues, research into the ancient Indian spice turmeric, commonly used in curry powder, has flourished. This spice, derived fro
m the roots of Curcuma longa, a yellow flowering plant native to the monsoon forests of South East Asia, possesses surprising therapeutic properties that may help explain India’s low Alzheimer’s rates.
In the early 2000s nutritionists noticed that turmeric’s most active ingredient, a compound known as curcumin, dismantles beta-amyloid plaques in a petri dish.5 A few years later, Fusheng Yang, a neurologist at the University of California Los Angeles, fed curcumin to Alzheimer’s mice and showed that it does indeed enter the brain and destroy plaques.6 Further tests found that curcumin might even stop tangles forming. Following this work, in 2013, Muaz Belviranli at Selçuk University, Turkey, demonstrated that curcumin fed to old rats improved their spatial memory and reduced the cellular damage associated with ageing.7 To date, there are more than 1,000 published studies with similar findings, and researchers have spent the last decade eagerly trying to reproduce the effects in humans.
The results, unfortunately, remain speculative. In 2006 researchers at the National University of Singapore tested 1,010 elderly Asians–Chinese, Malays and Indians–aged sixty to ninety-three, and discovered that those who ate curry ‘often or very often’ scored higher on cognitive tests than those who ‘never or rarely’ did.8 But with such a vast age range and diverse ethnic mix it’s hard to rule out other influences. The data from Alzheimer’s patients has been equally ambiguous, with only a few studies showing positive effects. Nevertheless, since most human studies have measured curcumin’s effect in months, not years, the evidence from cell and animal models needn’t be dismissed. In fact many scientists believe the prime obstacle is the spice’s transience: since curcumin doesn’t absorb well into blood (over 60 per cent is excreted in stool) the question remains whether it would have an impact if its blood levels could be raised and maintained.
Mark Taylor, a chemist at the University of Lancaster, England, is now trying to develop methods to bind curcumin on to the surface of nanoparticles: a form of nanotechnology made using molecules of fats, proteins, iron, even gold.9 This so-called nanocurcumin will hopefully increase curcumin’s absorption in the body, allowing more of it to reach the brain and work its magic. If it ever is concluded that curcumin guards Ballabgarh’s population from Alzheimer’s, we shall look back in wonderment at the measures we employed to mimic something so simple.
As it happens, Chand and his elderly companions consume turmeric often. In India the average consumption of curcumin is 80–200 milligrams per day (I myself can’t remember the last time I ate a meal containing the ingredient). In clinical trials researchers used doses of up to 4 grams a day for six to twelve months. When compared to a lifetime of cultural habit, though, even this dose might be too little too late, and so it’s difficult to draw any firm conclusions about curcumin’s therapeutic value–larger, lengthier, more sophisticated trials are required. But still, Ganguli told me the evidence is encouraging, and she’s as sceptical by nature as they come.
This story speaks to a higher truth not mentioned enough. Science doesn’t seek to prove hypotheses; it seeks to disprove them. Every finding has scores of older, closely related findings trailing behind, each having been disproved, amending the scientific narrative. Even completely new discoveries must be fallible in some way, ready to be updated when a better idea comes along. Science orbits the truth; it doesn’t live there. The twentieth-century philosopher Karl Popper understood this better than anyone. He’s famous for proclaiming that a discovery ‘must be falsifiable: and in so far as it is not falsifiable, it does not speak about reality’.10 But I’ve always preferred something else he said: ‘Science must begin with myths, and with the criticism of myths.’ Is the feeling that Chand’s and the other elders’ lifestyle protects them from Alzheimer’s just that–a feeling, speculation, a myth?
Possibly. Only when Ganguli and others have falsified and criticised enough will we know for certain. But that scientists are now combing the world for answers fills me with hope. It shows just how far we are willing to go.
21
Clues from Colombia
Nature never draws a line without smudging it.
Sir Winston Churchill, Great Contemporaries, 1937
THE PLANE TOUCHED down with a gentle thud and slowed to greet the terminals of José María Córdova Airport. I collected my suitcase and caught a bus heading north-west to Medellín, the second-largest city in Colombia. This is a country of coffee-lovers and football fanatics and fierce national pride. It’s also home to the largest population of Alzheimer’s victims on the planet.
Over three centuries, some 5,000 people spread among twenty-five Colombian families have been affected. They have what the locals call La Bobera–the foolishness. In reality, they possess a genetic mutation that’s now recognised as the most common cause of early-onset Alzheimer’s: the Paisa mutation, named after the people of the region. This cursed mishap of DNA sprang from obscurity to global recognition in 1996, after being identified by a team of US researchers.1 But it was a young Colombian neurologist named Francisco Lopera who found the families, and risked much to help them.
As a trainee neurologist at Medellín’s University of Antioquia, Lopera wasn’t quite sure where his interests lay. Then, one day in 1984, a forty-seven-year-old man from Belmira, a sleepy town in the nearby mountains, walked into Lopera’s office with a bizarre tale. He had been struck by an unnatural memory loss, he told Lopera. The man–let’s call him Mr Rodríguez–believed it was the maldición, an evil spell that now befell nine others in his family. He’d been to see the local witch doctors for various potions and tonics, but they hadn’t worked. He sought Lopera’s help as a last resort, for many in the town remained superstitious and believed it was a form of paranormal retribution. The family must have done something wicked, they thought. Perhaps they had touched the ‘bad tree’, or stolen from the church. But Lopera urged Rodríguez to dismiss such claims, and travelled with him to Belmira to examine the rest of the family.
When he returned, Lopera still wasn’t sure about the diagnosis. Shortly after, however, he was visited by a woman of the same age from another mountain town, called Angostura, where seventy people were affected with the same thing. Then fourteen more surfaced in the town of Yarumal, less than twenty kilometres away.
Lopera didn’t as yet know it was Alzheimer’s. That certitude arrived in 1995, when a man from Angostura donated his brain to the university and Lopera, together with Alison Goate (our heroine geneticist from chapter five) found that not only was it filled with plaques and tangles, but it also harboured another genetic mutation to add to the growing list.
With that, Lopera informed every family of the maldición’s true cause. He told them to expect many scientists from America and beyond to visit their secluded homes. By giving blood samples and having memory tests, he said, they would be helping themselves and the research into a disease that was, to their astonishment, currently enveloping the globe.
But this wasn’t Carol Jennings’s living room. Guerrilla warfare was a material problem in this part of Colombia. The FARC, a left-wing terrorist group, had been drug trafficking and murdering people for the past fifty years. Their ‘revolutionary’ methods involved kidnapping, attacking civilians, using child soldiers, and assassinating indigenous people–all of which strangled Colombia’s growth into a prosperous and free society. In some areas the violence was so bad that many people fled into the outskirts of Medellín itself. Lopera took every precaution he could, often sending scouts ahead to gather families on the quiet.
It didn’t always work, of course. During one excursion a nurse was kidnapped by guerrillas and detained for eight days. Incredibly, she was released and permitted to continue when the guerrilla chief realised that his own mother had Alzheimer’s. But such mitigation only extended so far, and so Lopera and his team stopped visiting towns like Angostura for years. Only in the mid-2000s did the scientists venture out once more, when conservative President Álvaro Uribe–whose own father was murdered by the FARC–used the
military to force the guerrillas into retreat (today, Uribe’s policies have made it safe for foreign investment in Colombia, tremendously improving the country’s economy). Finally, Lopera could ascertain enough data to turn La Bobera into one of the world’s most enlightening groups of Alzheimer’s patients.
Carlos Díaz was among them. When he wasn’t fixing cars as the local mechanic, he was polishing his favourite truck and watching football with his two sons and four daughters. His wife Maria knew him as a man of strong work ethic and high spirits; but when Carlos turned forty-seven, everything changed. ‘He started looking at me like he was lost,’ Maria told me at her home in the hills bordering Medellín. I had travelled there with Lucía Madrigal, a psychologist who’s worked with Lopera since the beginning, and Gabriel Aristizábal, my translator. ‘One day, he went outside to clean his truck, and walked twenty-five blocks away. If we hadn’t searched for him he’d probably be in the middle of the mountains. To be honest, I thought it was something supernatural. Weird things were happening in the house: the lights were going off, things kept moving from place to place. So I just took care of him, because he wasn’t a difficult patient.’
Maria emitted a distinct calm–a toughness, an armour–that quickly explained itself. In the next room, Maria’s forty-five-year-old daughter, Alejandra, was being informed of my visit. She too has Alzheimer’s–as did one of her sisters, Camila, who died a month earlier. Providence has yet to reveal who else in the family has Alzheimer’s. Six of Carlos’s twelve siblings had been affected, and all had become sick in their mid-forties. But while Maria now accepts it as a disease, her sons cannot. When Camila died, they persuaded their sisters to change religion–from Catholic to Protestant–in the hope that whatever spirit was tormenting the family would now be appeased, allowing the illness to die with Camila.
In Pursuit of Memory Page 22