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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Society

Debt Trap: Why South Korean Economics Explains Squid Game

Crunching the numbers of South Korea's personal and household debt offers a glimpse into what drives the win-or-die plot of the Netflix hit produced in the Asian country.

In the Netflix series, losers of the game face death

Yip Wing Sum

-Analysis-

SEOUL — The South Korean series Squid Game has become the most viewed series on Netflix, watched by over 111 million viewers and counting. It has also generated a wave of debate online and off about its provocative message about contemporary life.

The plot follows the story of a desperate man in debt, who receives a mysterious invitation to play a game in which the contestants gamble their lives on six childhood games, with the winner awarded a prize of 45.6 billion won ($38 million)... while the losers face death.


It's a plot that many have noted is not quite as surreal as it sounds, a reflection of the reality of Korean society today mired in personal debt.

Seoul housing prices top London and New York

In the polished streets of downtown Seoul, one sees endless cards and coupons advertising loans scattered on the ground. Since the outbreak of the pandemic, as the demand for loans in South Korea has exploded, lax lending policies have led to a rapid increase in personal debt.

According to the South Korean Central Bank's "Monetary Credit Policy Report," household debt reached 105% of GDP in the first quarter of this year, equivalent to approximately $1.5 trillion at the end of March, with a major share tied up in home mortgages.

Average home loans are equivalent to 270% of annual income.

One reason behind the debts is the soaring housing prices. In Seoul, home to nearly half of the country's population, housing prices are now among the highest in the world. The price to income ratio (PIR), which weighs the average price of a home to the average annual household income, is 12.04 in Seoul, compared to 8.4 in San Francisco, 8.2 in London and 5.4 in New York.

According to the Korea Real Estate Commission, 42.1% of all home purchases in January 2021 were by young Koreans in their 20s and 30s. For those in their 30s, the average amount borrowed is equivalent to 270% of their annual income.

Playing the stock market

At the same time, the South Korean stock market is booming. The increased demand to buy stocks has led to an increase in other loans such as credit. The ratio for Korean shareholders conducting credit financing, i.e. borrowing from securities companies to secure stock holdings, had reached 21.4 trillion won ($17.7 billion), further increasing the indebtedness of households.

A 30-year-old Seoul office worker who bought stocks through various forms of borrowing was interviewed by Reuters this year, and said he was "very foolish not to take advantage of the rebound."

In addition to his 100 million won ($84,000) overdraft account, he also took out a 100 million won loan against his house in Seoul, and a 50 million won stock pledge. All of these demands on the stock market have further exacerbated the problem of household debt.

42.1% of all home purchases in January 2021 were by young Koreans in their 20s and 30s

Simon Shin/SOPA Images/ZUMA

Game of survival

In response to the accumulating financial risks, the Bank of Korea has restricted the release of loans and has announced its first interest rate hike in three years at the end of August.

But experts believe that even if banks cut loans or raise interest rates, those who need money will look for other ways to borrow, often turning to more costly institutions and mechanisms.

This all risks leading to what one can call a "debt trap," one loan piling on top of another. That brings us back to the plot of Squid Game, "Either you live or I do." South Korean society has turned into a game of survival.

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