A thief of memory stalks a Colombian family


POSTED: Wednesday, June 02, 2010

YARUMAL, Colombia >> Tucked away on a steep street in this rough-hewn mountain town, an old woman found herself diapering her middle-age children.

At frighteningly young ages, in their 40s, four of Laura Cuartas' children began forgetting and falling apart, assaulted by what people here have long called La Bobera, the foolishness. It is a condition attributed, in hushed rumors, to everything from touching a mysterious tree to the revenge of a wronged priest.

It is Alzheimer's disease, and at 82, Cuartas, gray raisin of a face grave, takes care of three of her children undone by dementia.

One son, Dario, now 55, babbles incoherently, shreds his socks and diapers, and squirms so vigorously he is sometimes tied to a chair with baggy blue shorts.

A daughter, Maria Elsy, a nurse who, at 48, started forgetting patients' medications, and whose irrational rages made her attack a sister who bathed her, is now a human shell, mute, fed by a nose tube.

Another son, Oderis, 50, denies that his memory is dying, that he remembers to buy only one thing at a time: milk, not milk and plantains. If he gets Alzheimer's, he says, he will poison himself.

“;To see your children like this ...,”; Cuartas said. “;It's horrible, horrible. I wouldn't wish this on a rabid dog. It is the most terrifying illness on the face of the earth.”;

For generations, the illness has tormented these and thousands of others among a sprawling group of relatives: the world's largest family to experience Alzheimer's disease. Now, the Colombian clan is center-stage in a potentially groundbreaking assault on Alzheimer's, a plan to see if giving treatment before dementia starts can lead to preventing Alzheimer's altogether.

Most family members come from one Andes mountain region, Antioquia. Geography, and Basque ancestry, have isolated people here, who call themselves paisas, countrymen. Over three centuries, many in this clan of 5,000 people have inherited a single genetic mutation guaranteeing that they will develop Alzheimer's young. Large families, and intermarriage, have accelerated the disease's spread. Cuartas' fourth debilitated child in Medellin, Carlos Alberto Villegas, a former livestock trader and guitar serenader now often fed by baby bottle, married a distant cousin. His mother-in-law is an addled ghost; three of his wife's 11 siblings, so far, are developing dementia.

With Alzheimer's in both parents' families, Carlos Alberto Villegas' three children, could face extraordinary risk.

One, Natalia, 22, asks: “;How long have I got, till I'm 35? There's no way out.”;

Memories begin failing in one's 40s, occasionally as early as 32. By 47, on average, full-blown Alzheimer's develops, so aggressive that it steals sensation and function in agonizingly quickly.

Their form of Alzheimer's, early-onset, was once considered too different to provide clues about far more common late-onset Alzheimer's, which has unknown causes and primarily affects people over 65.

But it turns out that both forms produce nearly identical brain changes and symptoms. So now, scientists will test as-yet-unproven treatments on Colombians genetically destined for Alzheimer's but not yet showing symptoms. They will administer a drug or vaccine—which is being determined—and see if it prevents memory loss or brain atrophy.

If their disease can be halted, that could generate treatments to protect millions worldwide from common Alzheimer's.

For decades, Alzheimer's has repeatedly resisted attempts to treat it. Current drugs, aimed at people who are already impaired, show little, if any, benefit. Now scientists want to attack earlier, before symptoms appear.

New findings show “;the brain is badly damaged by the time they have dementia,”; said Dr. John C. Morris, an Alzheimer's researcher at Washington University in St. Louis. “;Perhaps the reason our therapies have been ineffective or mostly ineffective is that we're administering them too late.”;

Alzheimer's afflicts 5.3 million Americans and 30 million people worldwide, numbers that some predict will double or triple by 2050.

“;We can't wait to try to do prevention until we are absolutely certain what causes”; the disease, said Neil Buckholtz, chief of dementias of aging at the National Institute on Aging. “;This public health emergency,”; he said, is “;just going to get out of control if we don't do something.”;

But preventive research is difficult. Participants should be people guaranteed, or highly likely, to develop dementia, and with common Alzheimer's identifying such people is challenging because the disease's cause is unknown. Also, because people would not be sick when treated, potential negative side effects of drugs are especially worrisome.

Colombia provides the best chance. People with the mutation always develop Alzheimer's, and researchers know roughly when. They can give treatment about five years before expected memory loss, then see if brain changes or symptoms occur later or not at all.

Since Colombians with Alzheimer's are young, without many old-age ailments, they have “;cleaner brains that can give a better picture”; of whether drugs work, Buckholtz said.

And the extended family's single location, large size and similar lifestyles provide enough comparable participants for solid scientific data.

“;This is the only place in the world where we can find a family like this, where it's possible to do prevention therapy more easily,”; said Dr. Francisco Lopera, a Medellin neurologist who identified the family's illness three decades ago and helped discover its cause, an altered protein on the presenilin 1 gene on chromosome 14: the Paisa mutation.

Scientists consider Colombians not only valuable subjects but deserving ones.

“;We'd be giving people at the highest imminent risk of Alzheimer's access to treatment they wouldn't otherwise have,”; said a project leader, Dr. Eric M. Reiman, executive director of Banner Alzheimer's Institute in Phoenix.

Scientists are recruiting participants, hoping to start testing treatments next year. Family members without symptoms, roughly 38 to 45 years old, will be gene-tested, given treatment or placebos, and monitored with memory testing, brain scans and other measures.

A companion American trial will involve 60- to 80-year-olds with another rare trait: two copies of a different gene, which does not cause, but substantially increases risk of common late-onset Alzheimer's.

The treatment, likely to be chosen by independent experts, could be something that failed with already-demented patients or something new. It will attack a protein, beta-amyloid, considered a culprit by many scientists because it creates plaques, deposits between nerve cells. The treatment could be a drug that destroys or prevents plaques, or a vaccine that contains or encourages production of anti-amyloid antibodies.

The project was not always an easy sell.

For years, “;I've been sort of shopping this around,”; said Dr. Kenneth S. Kosik, a neuroscientist at the University of California, Santa Barbara, who has long studied the family. “;People would get interested, then realize there are huge logistical hurdles. Medellin was a murder capital of the world. Nobody wanted to even talk about going to Colombia.”;

Challenges included a relatively uneducated population with misconceptions about Alzheimer's, that it was transmitted through sex with already-mad women, or from blood of a sufferer's self-inflicted scratches. Relatives, who handle caregiving here, sometimes take desperate measures, like locking the “;affecteds”; in rooms to prevent wandering.

Marriage options were often limited, and many did not understand that intermarriage could increase chances of passing Alzheimer's to children. When Laura Cuartas' son Carlos Alberto Villegas married his distant cousin Blanca Nelly Betancur, people knew La Bobera was in the extended family, which some considered “;the clan of the bobos.”; But while Carlos Alberto Villegas told his bride-to-be that his father “;had become foolish,”; she said, back then, “;Carlos was healthy.”;

Others talk of drastic reactions if they learn they are mutation-carriers.

“;I'd kill myself,”; said Carlos Alberto Villegas' brother-in-law, Albeiro Betancur, 40, a bus driver with four children. “;I'd throw myself under a train.”;

Such reactions, plus the lack of genetic counseling here, are why people gene-tested by Lopera, the Medellin neurologist, are not told if they will get Alzheimer's. Even he knows carriers only by computer code, not by name.

American research participants in trials of genetically-driven diseases sometimes learn their genetic status, and questions arose about testing drugs on Colombians who are unaware they are carriers. The answer was to give all participants something, so mutation-carriers are not revealed. Placebos will be given to noncarriers; treatment or placebos to carriers.

Scientists must ensure the Colombians are not exploited or harmed. Some past drug trials on already-sick Alzheimer's patients were stopped because patients developed brain inflammation or risked heart problems. If scientists here test treatments intended for 80-year-old Alzheimer's patients, doses must be calibrated for 40-year-olds, some of them potentially pregnant women. And testing drugs on people who are not yet sick is especially risky.

“;We're going to be treating people who are completely healthy,”; Kosik said. “;The nightmare scenario is obviously that there's a serious side effect.”;

There were other challenges: upgrading brain-scanning and other equipment, and persuading drug companies to accept the financial and safety risks of sponsoring such research.

“;Two years ago,”; said Dr. Pierre N. Tariot, a project leader who directs the Banner Alzheimer's Institute's memory disorders center, “;most scientists would have said this is not feasible,”; considering it “;science fiction.”;

Now, scientists are recruiting drug-industry sponsors for the $50 million trial. They currently have $8 million from donors.

Some companies envision testing new treatments; others envision recovering investment in therapies that failed with already-demented people, but might work when tried earlier.

“;Prevent even one early-onset patient from getting the disease, that's a major victory,”; said Dale Schenk, chief scientific officer for the Elan Corporation, which has tested therapies on common Alzheimer's patients. “;It's not even debatable whether this should be done. It has to be done.”;

Researchers will also explore when Alzheimer's begins, and why.

They will examine which brain changes, or biomarkers, precede symptoms, said Reiman, the project co-leader. If brain shrinkage, brain activity or beta-amyloid levels are identified as definitive biomarkers, doctors may be able to treat those, the way they treat cholesterol to prevent heart disease.

Scientists will also intensively study 40 18- to 25-year-olds to see if brain changes appear in people that young. If they do, children 8 to 17 will be studied.

A new memory test catches an early symptom: remembering only one characteristic of something. By age 35, Paisa-mutation carriers “;may remember seeing an apple, but not remember it's in the fridge,”; said a psychologist, Mario Parra, who created the test, in which people shown colored shapes must recall both the shapes and colors.

Scientists, unveiling the project here, recently rode into Angostura, ancestral home of many family members.

“;First time I've seen gringos come to town,”; a villager remarked.

Villages like Angostura had often been too dangerous.

Once, a nurse assisting Lopera, Lucia Madrigal, was kidnapped by guerrillas while collecting blood for gene testing. “;I do not care how long you retain me,”; she said, but “;take care of the samples.”;

She was released eight days later (guerrillas chilled the blood in a river), but Lopera's team stopped visiting some villages for years. During that time, Madrigal visited Angostura only when asked by a guerrilla boss. His mother had Alzheimer's.

With Angostura still risky, Lopera scheduled a brief visit, sending advance staff members instructed not to disclose that Americans were coming.

As a strong sun sliced the sky and rifle-bearing army soldiers watched, family members squeezed into a squat building, Catholic maxims on walls.

“;You may think you live in a very small town in a remote corner of the world,”; Kosik said. “;But Alzheimer's is of concern to people all over the world, and this town is very special.”;

Questions flew.

“;Give us this medicine, and then will we ever hear from you again?”; Scientists reassured them.

What about economic assistance? Tariot said pharmaceutical sponsors would be asked to provide needs like antibiotics, food and much-requested adult diapers.

For years, Lopera has been frustrated that he could provide only support, and medication for ancillary Alzheimer's symptoms like seizures and sleeplessness. Some, like Albeiro Betancur, Carlos Alberto Villegas' brother-in-law, said he had stopped participating in Lopera's previous research, because there was “;no prospect of any cure.”;

But this project held promise, many family members said. While some, like Laura Cuartas' daughter, Gloria, who helps care for her demented siblings, worried about “;damage that can be done”; by side effects, Betancur and others welcomed the possibility of “;taking something that might help.”;

Potential results are years away, of course, as more relatives face the devastating disease.

Recently, Lopera examined Laura Cuartas' son, Oderis Villegas, whose fading memory makes him carry calendars, writing each night, “;do not cross out tomorrow.”;

But for Lopera, Oderis Villegas, studiously groomed in yellow shirt and polished shoes, puffed with bravado, giddily following instructions to hop, whistle, touch his nose.

“;I'm the big help in the house; that's why I don't work,”; he said. “;I feel fine every day. In every sense.”;

“;When were you born?”; Lopera asked.

“;April 1960.”;

“;How old are you?”;

“;Close to 70, right?”;

“;You have a good memory?”;

“;Yes, sir.”;

Lopera listed three sentences: “;The boy walks down the street,”; “;The man drinks coffee,”; “;Oranges grow on trees.”;

“;What was the first?”;

“;The boy drinks coffee.”;

“;The second?”;

“;The children walk on trees.”;

Asked about his Alzheimer's risk, Oderis Villegas said, “;I don't have it,”; laughing.

“;Just by chance and when I am distracted by people or something,”; he said, “;I may forget, but that is very rare. For anyone to say that I have the beginning of Alzheimer's, no.”;