Future

In "Cursed" Colombia Region, Clues To Alzheimer's Cause

Tests in a region in Colombia with widespread, recurring and inherited Alzheimer's may help researchers understand why the disease occurs and has thwarted treatments for so long.

Yaned's mother has Alzheimer's and can no longer walk on her own.
Yaned's mother has Alzheimer's and can no longer walk on her own.
Jesus Mendez

ANTIOQUIA — If Macondo, the fictitious district in Gabriel García Márquez's One Hundred Years of Solitude, existed, it would have to be in this northeastern corner of Colombia. The unusual prevalence of Alzheimer's Disease striking this area is reminiscent of the "plague of sleeplessness" or "disease of forgetfulness" cited by the Indian woman in the late Colombian novelist's masterpiece. She describes an endemic sleeplessness that in time morphs into acute forgetfulness. There is no exhaustion or sleep for the sufferer, but a gradual loss of memory through one sleepless night after another, of childhood, of names and then of the very notion of all things.

You sink into a state of idiocy without past or origin, though in the novel, García Márquez is not describing Alzheimer's, which he coincidentally suffered from before dying.

Macondo could be any of several villages in the Antioquia region north of Bogotá, which are both damned and paradoxically a source of hope for understanding and treating Alzheimer's. Today some 5,000 members of 25 families with a shared ancestry and carrying the paisa or Antioquian mutation live in this area. It seems to exist exclusively in them and leads to Alzheimer's developing rapidly, usually before the patient reaches the age of 50. Experts hope that it might reveal secrets about the condition that explain why so many attempts at treatment have thus far failed.

A mystery disease

No treatment exists for this condition, though it was identified over 100 years ago, and that is in great part because doctors do not know precisely how it is originates.

In addition to memory loss, two types of lesion on the brain characterize the illness: amyloid plaques and neurofibrillary tangles (NFTs) or abnormal protein deposits. The plaques have become popular with researchers, for several reasons. While only one per cent of Alzheimer's sufferers are considered genetic inheritors — like those of Antioquia — the mutations found in them are always related to three genes related to the amyloid protein. They favor its abnormal production and tendency to deposit.

Another cause of interest was that the amyloid plaques appear in all Alzheimer's sufferers, even years before the infirmity appears. When the plaques are created in lab mice, they produce many of the symptoms seen in patients. Lastly, the abnormal amyloid is able to change the configuration around it, provoking lesions that extend across the brain, at least in mice. The illness appears directly linked to the amyloid and would presumably disappear, if this could be eliminated.

Yet no drugs have managed to do this, even when they remove the plaques. The symptoms have always persisted, which led some scientists, not all, to think that the amyloid plaques might be complementary or symptomatic of the ailment. The amyloid hypothesis has in part come back to the fore with hopes are being placed squarely on the unusual situation in this part of Colombia, where clinical trials are being carried out by the neurologist Francisco Lopera, of the neurosciences group at the Antioquia University.

"We never had hopes that the treatments used would work," says Lopera. "The anti-amyloids were used when the patient had reached the stage of dementia and that way they are bound to fail, because the damage from amyloid is inflicted many years earlier. You have to clean it before there is deterioration."

Failed tests on healthy

Preventive tests may be a way then: testing drugs on people without symptoms but who will develop the illness. But how do you identify them, when the immense majority of people who develop Alzheimer's do so unexpectedly, without anticipatory signs. The illness incubates in absolute silence.

This is where the so-called "Antioquian curse" comes in. Within a few square kilometers, hundreds of people are among the carrier families. They have no symptoms but are already sentenced. They will suffer what locals call the "Piedrahita foolishness," a reference to one of 25 families carrying the mutation thought to originate in their ancestors, a Basque couple.

Lopera describes the area as a "veritable living lab" that will allow researchers to identify and treat the type of volunteer needed for such studies. In ordinary conditions the same people would know nothing of their fate. But are the results of this family Alzheimer's pertinent to the sporadic type? Lopera believes so. "There are small differences," he says, citing the number of amyloid types. "(But) essentially they are very similar. I am hopeful the family type will be a window for knowing the world of Alzheimer's."

Lopera's tests began in 2013 and have now gathered their volunteers. They will total 300, of whom 200 will have the mutation. Certain conditions include being between 30 and 60 years old, not showing any Alzheimer's symptoms nor knowing whether or not they are carriers. Half will be given an anti-amyloid drug — Crenezumab —" and the other half, placebos. The team will make a preliminary evaluation in 2018 and publish its results around 2021.

That is when it will be known whether or not the drugs have reduced the amyloid plaques carriers, which can begin to accumulate from age 28. In that case the symptoms will have been prevented or at least delayed. As Alzheimer's is a disease of old age, Lopera says that "just pushing back the symptoms five years would halve the prevalence of Alzheimer's." If the test fails, would that be the end of the amyloid approach? No, says Lopera. "What we are doing is secondary prevention, because these people already have amyloid. You would have to try it in primary prevention too, before deposits are formed."

The ever-closer dream of a remedy

Alberto Lleó, head of the Neurology Service's Memory Unit at the Sant Pau hospital in Barcelona, says the Antioquia study holds serious potential. Sporadic Azheimer's does differ from the genetic form, he says, but "the results may well be applicable." Lleó also refers to the promising results of anti-amyloid drugs on people with plaques but very light symptoms, which boost the amyloid perspective on Alzheimer's.

Similar studies to the one in Antioquia are being carried out in other parts of the world. One is the DIAN Observational Study, which recruits volunteers with different mutations. Another is A4, a major project to identify 1,000 volunteers with plaques but without known symptoms or mutations. These too are expected to be completed around 2020.

"We should be very close to the first treatment within five years," says Lleó. "Perhaps not to cure the illness but modify its course, which is revolutionary in itself." Yet given the complexity of this illness, he says, treatment will not consist merely in anti-amyloid drugs but likely be similar to AIDS, "with various drugs acting independently along different paths." There may be a cocktail of drugs working separately on amyloid plaques and the tangles, and acting as cognitive stimulants.

A Basque country curse too?

In the Basque region in northern Spain, the Piedrahita are one of the 25 families affected by the Antioquian mutation. Lopera has traced their family origins to 1745, when a couple came to the Colombian region, probably from the Basque country. Their descendants now number some 5,000. "What we don't understand is why the mutation hasn't been found in Europe," Lopera notes.

The first case he says he observed was as a young researcher of a patient who had memory loss at the age of 47 and "curiously his father and grandfather had the same symptoms. And that was before anyone had identified a gene relating to Alzheimer's." More cases came in. "Just out of typical student curiosity, I used to go to the first case's home village to reconstruct the histories of these dementias," he recalls.

He says it was seen as a curse at the time. "In one village people said a priest had damned them for stealing in the parish. In another, they related this to natural phenomena, like touching an abnormal tree. Or they would simply ascribe it to the evil eye."

With scientific explanations the magical attributions have practically disappeared, allowing some families to get better treatment. "Before they might even throw (relatives) out the house because they couldn't understand their aggressive conduct or delirious fits," he says.

Indeed, in what might be described as folklore, we can learn how locals lived with and observed the symptoms of Alzheimer's throughout the centuries. The progression is precisely described, beginning with the "repetitive phase" or repetidora ("they repeat the same story, ask the same question"), which precedes the caminadera (wandering aimlessly), the acostadera (increasingly bed-ridden) and the orinadera (incontinence), and ending with the moridera: death.

People have become accustomed to their regional tragedy, says Lopera. He recalls a patient's relative saying "God knows how He does things: He makes only one half of the family ill so the other half can take care of the carriers."

Another patient once told Lopera: "You don't know the good thing about Alzheimer's, doctor..." No, he admitted, he'd seen little good from it. The bad thing, the patient agrees, is that it is incurable, but "the good thing is it's not contagious."

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Future

7 Ways The Pandemic May Change The Airline Industry For Good

Will flying be greener? More comfortable? Less frequent? As the world eyes a post-COVID reality, we look at ways the airline industry has been changing through a pandemic that has devastated air travel.

Ready for (a different kind of) takeoff?

Carl-Johan Karlsson

It's hard to overstate the damage the pandemic has had on the airline industry, with global revenues dropping by 40% in 2020 and dozens of airlines around the world filing for bankruptcy. One moment last year when the gravity became particularly apparent was when Asian carriers (in countries with low COVID-19 rates) began offering "flights to nowhere" — starting and ending at the same airport as a way to earn some cash from would-be travelers who missed the in-flight experience.

More than a year later today, experts believe that air traffic won't return to normal levels until 2024.


But beyond the financial woes, the unprecedented slowdown in air travel may bring some silver linings as key aspects of the industry are bound to change once back in full spin, with some longer-term effects on aviation already emerging. Here are some major transformations to expect in the coming years:

Cleaner aviation fuel

The U.S. administration of President Joe Biden and the airline industry recently agreed to the ambitious goal of replacing all jet fuel with sustainable alternatives by 2050. Already in a decade, the U.S. aims to produce three billion gallons of sustainable fuel — about one-tenth of current total use — from waste, plants and other organic matter.

While greening the world's road transport has long been at the top of the climate agenda, aviation is not even included under the Paris Agreement. But with air travel responsible for roughly 12% of all CO2 emissions from transport, and stricter international regulation on the horizon, the industry is increasingly seeking sustainable alternatives to petroleum-based fuel.

Fees imposed on the airline industry should be funneled into a climate fund.

In Germany, state broadcaster Deutsche Welle reports that the world's first factory producing CO2-neutral kerosene recently started operations in the town of Wertle, in Lower Saxony. The plant, for which Lufthansa is set to become the pilot customer, will produce CO2-neutral kerosene through a circular production cycle incorporating sustainable and green energy sources and raw materials. Energy is supplied through wind turbines from the surrounding area, while the fuel's main ingredients are water and waste-generated CO2 coming from a nearby biogas plant.

Farther north, Norwegian Air Shuttle has recently submitted a recommendation to the government that fees imposed on the airline industry should be funneled into a climate fund aimed at developing cleaner aviation fuel, according to Norwegian news site E24. The airline also suggested that the government significantly reduce the tax burden on the industry over a longer period to allow airlines to recover from the pandemic.

Black-and-white photo of an ariplane shot from below flying across the sky and leaving condensation trails

High-flying ambitions for the sector

Joel & Jasmin Førestbird

Hydrogen and electrification

Some airline manufacturers are betting on hydrogen, with research suggesting that the abundant resource has the potential to match the flight distances and payload of a current fossil-fuel aircraft. If derived from renewable resources like sun and wind power, hydrogen — with an energy-density almost three times that of gasoline or diesel — could work as a fully sustainable aviation fuel that emits only water.

One example comes out of California, where fuel-cell specialist HyPoint has entered a partnership with Pennsylvania-based Piasecki Aircraft Corporation to manufacture 650-kilowatt hydrogen fuel cell systems for aircrafts. According to HyPoint, the system — scheduled for commercial availability product by 2025 — will have four times the energy density of existing lithium-ion batteries and double the specific power of existing hydrogen fuel-cell systems.

Meanwhile, Rolls-Royce is looking to smash the speed record of electrical flights with a newly designed 23-foot-long model. Christened the Spirit of Innovation, the small plane took off for the first time earlier this month and successfully managed a 15-minute long test flight. However, the company has announced plans to fly the machine faster than 300 mph (480 km/h) before the year is out, and also to sell similar propulsion systems to companies developing electrical air taxis or small commuter planes.

New aircraft designs

Airlines are also upgrading aircraft design to become more eco-friendly. Air France just received its first upgrade of a single-aisle, medium-haul aircraft in 33 years. Fleet director Nicolas Bertrand told French daily Les Echos that the new A220 — that will replace the old A320 model — will reduce operating costs by 10%, fuel consumption and CO2 emissions by 20% and noise footprint by 34%.

International first class will be very nearly a thing of the past.

The pandemic has also ushered in a new era of consumer demand where privacy and personal space is put above luxury. The retirement of older aircraft caused by COVID-19 means that international first class — already in steady decline over the last decades — will be very nearly a thing of the past. Instead, airplane manufacturers around the world (including Delta, China Eastern, JetBlue, British Airways and Shanghai Airlines) are betting on a new generation of super-business minisuites where passengers have a privacy door. The idea, which was introduced by Qatar Airways in 2017, is to offer more personal space than in regular business class but without the lavishness of first class.

Aerial view of Rome's Fiumicino airport

Aerial view of Rome's Fiumicino airport

commons.wikimedia.org

Hygiene rankings  

Rome's Fiumicino Airport has become the first in the world to earn "the COVID-19 5-Star Airport Rating" from Skytrax, an international airline and airport review and ranking site, Italian daily La Repubblica reports. Skytrax, which publishes a yearly annual ranking of the world's best airports and issues the World Airport Awards, this year created a second list to specifically call out airports with the best health and hygiene standards.

Smoother check-in

​The pandemic has also accelerated the shift towards contactless traveling, with more airports harnessing the power of biometrics — such as facial recognition or fever screening — to reduce touchpoints and human contact. Similar technology can also be used to more efficiently scan physical objects, such as explosive detection. Ultimately, passengers will be able to "check-in" and go through a security screening anywhere at the airports, removing queues and bottlenecks.

Data privacy issues

​However, as pointed out in Canadian publication The Lawyer's Daily, increased use of AI and biometrics also means increased privacy concerns. For example, health and hygiene measures like digital vaccine passports also mean that airports can collect data on who has been vaccinated and the type of vaccine used.

Photo of planes at Auckland airport, New Zealand

Auckland Airport, New Zealand

Douglas Bagg

The billion-dollar question: Will we fly less?

At the end of the day, even with all these (mostly positive) changes that we've seen take shape over the past 18 months, the industry faces major uncertainty about whether air travel will ever return to the pre-COVID levels. Not only are people wary about being in crowded and closed airplanes, but the worth of long-distance business travel in particular is being questioned as many have seen that meetings can function remotely, via Zoom and other online apps.

Trying to forecast the future, experts point to the years following the 9/11 terrorist attacks as at least a partial blueprint for what a recovery might look like in the years ahead. Twenty years ago, as passenger enthusiasm for flying waned amid security fears following the attacks, airlines were forced to cancel flights and put planes into storage.

40% of Swedes intend to travel less

According to McKinsey, leisure trips and visits to family and friends rebounded faster than business flights, which took four years to return to pre-crisis levels in the UK. This time too, business travel is expected to lag, with the consulting firm estimating only 80% recovery of pre-pandemic levels by 2024.

But the COVID-19 crisis also came at a time when passengers were already rethinking their travel habits due to climate concerns, while worldwide lockdowns have ushered in a new era of remote working. In Sweden, a survey by the country's largest research company shows that 40% of the population intend to travel less even after the pandemic ends. Similarly in the UK, nearly 60% of adults said during the spring they intended to fly less after being vaccinated against COVID-19 — with climate change cited as a top reason for people wanting to reduce their number of flights, according to research by the University of Bristol.

At the same time, major companies are increasingly forced to face the music of the environmental movement, with several corporations rolling out climate targets over the last few years. Today, five of the 10 biggest buyers of corporate air travel in the US are technology companies: Amazon, IBM, Google, Apple and Microsoft, according to Taipei Times, all of which have set individual targets for environmental stewardship. As such, the era of flying across the Atlantic for a two-hour executive meeting is likely in its dying days.

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