An Ancient Cure for Alzheimer's?
July 14, 2017 - NYTimes

Eleanor Davis, Contributing Op-Ed Writer

In 2011, Ben Trumble emerged from the Bolivian jungle with a backpack containing hundreds of vials of saliva. He had spent six weeks following indigenous men as they tramped through the wilderness, shooting arrows at wild pigs. The men belonged to the Tsimane people, who live as our ancestors did thousands of years ago — hunting, foraging and farming small plots of land. Dr. Trumble had asked the men to spit into vials a few times a day so that he could map their testosterone levels. In return, he carried their kills and helped them field-dress their meat — a sort of roadie to the hunters.

Dr. Trumble wanted to find out whether the hunters who successfully shot an animal would be rewarded with a spike in testosterone. (They were.) As a researcher with the Tsimane Health and Life History Project, he had joined a long-running investigation into human well-being and aging in the absence of industrialization. That day when he left the jungle, he stumbled across a new and more urgent question about human health. He dropped his backpack, called his mom and heard some terrible news: His 64-year-old uncle had learned he had dementia, probably Alzheimer's.

In just a few short years, his uncle, a vibrant former lawyer, would stop speaking, stop eating and die. "I couldn't help my uncle," Dr. Trumble said, but he was driven to understand the disease that killed him. He wondered: Do the Tsimane suffer from Alzheimer's disease like we do? And if not, what can we learn from them about treating or preventing dementia?

"There is really no cure yet for Alzheimer's," Dr. Trumble told me. "We have nothing that can undo the damage already done." Why, he wondered, had billions of dollars and decades of research yielded so little? Perhaps major clues were being missed.

Dr. Trumble was trained as an anthropologist, and his field — evolutionary medicine — taught him to see our surroundings as a blip in the timeline of human history. He thinks it's a problem that medical research focuses almost exclusively on "people who live in cities like New York or L.A." Scientists often refer to these places as "Weird" — Western, educated, industrialized, rich and democratic — and point out that our bodies are still designed for the not-Weird environment in which our species evolved. Yet we know almost nothing about how dementia affected humans during the 50,000 years before developments like antibiotics and mechanized farming. Studying the Tsimane, Dr. Trumble believes, could shed light on this modern plague.

The Tsimane suffer from high infant-mortality rates, but those who reach adulthood live about as long as most other people, making it possible to measure their health outcomes up to age 90 and beyond. The Tsimane Project researchers have spent more than 15 years following their volunteers and providing medical treatment. They've found that Tsimane differ from the rest of us in many ways. For example, they have the cleanest arteries of any population that has ever been studied, meaning that they may be largely immune to heart disease.

Dr. Trumble was not the first member of the Tsimane Project to wonder about dementia in this population. In 2002, one of the group's founders, Michael Gurven, began testing mental fitness by asking older people to do puzzles. This and other cognitive-performance data piled up until 2015 — the year that Dr. Trumble's uncle died. That was when Dr. Trumble, Dr. Gurven and other researchers decided to dive into it.

Dr. Trumble was particularly interested in the ApoE4 gene, often called the Alzheimer's gene. Americans who carry two copies of the gene are more than 10 times as likely to develop the late-onset form of the disease. Dr. Trumble found something startling when he looked into the Tsimane data: Many of those with a copy of the gene seemed to perform better on the cognitive tests.

He mulled this paradox in his sunny lab back at Arizona State University. He had just returned from another trip to the Tsimane settlements, and a bit of Bolivia had come with him: an intestinal infection from the campylobacter bacteria and two nasty species of E. coli. "I got so sick that I almost missed my wedding," he said. This was not his first encounter with tropical parasites. Years before he had noticed what looked like a zit on his nose. When it kept growing, he realized it was a flesh-eating parasite called leishmania. Chemotherapy saved his nose, and perhaps his life.

"Getting parasitic infections gave me perspective," he said. At least 70 percent of the Tsimanes are infected with parasites — worms in their guts, invaders burrowing into their skin — at any given time. The same was likely true of our ancestors. He began to wonder: Could these infections change the way that genes affect our bodies?

Perhaps the ApoE4 gene provided a survival advantage in ancient environments. Today only about a quarter of us have a single copy of the ApoE4 gene, and only about two in a hundred carry a double dose. But DNA analysis of ancient bones shows that thousands of years ago, the ApoE4 genotype was ubiquitous in humans. The gene — which helps to generate cholesterol — might have been a crucial step in the development of our big, energy-hungry brains, and it may have played a key role in defending those brains from pathogenic invaders.

Dr. Trumble then looked at the data on the cognitive health of all the Tsimane volunteers who had tested positive for parasites. Sure enough, he found that Tsimane with infections were more likely to maintain their mental fitness if they carried one or two copies of the ApoE4 gene; for them, the "Alzheimer's gene" provided an advantage. For the minority who'd managed to elude parasitic infection, however, the opposite was true, and the ApoE4 gene was connected with cognitive decline, just as it is for people in industrialized countries.

"Humans co-evolved with a number of different parasites, but today, in our sedentary city life, we've removed those parasites from the mix," Dr. Trumble said. This could be what transformed the gene from an advantage into a liability.

As it happens, these findings dovetail with some new research from university labs. In papers released in 2016 and 2017, scientists looked at dementia in a new way — not just as a disease that results from the gradual breakdown of our cells, but as a disorder in which the brain turns against itself.

Years ago, while reporting a story about the Harvard Brain Tissue Resource Center, I had a chance to peer through a microscope at a slice of brain collected from a patient who'd died of Alzheimer's disease. The tissue was pocked with amyloid plaques that resembled black clouds. I also spied the tau tangles that look like hair clogging a drain and are characteristic of Alzheimer's pathology.

For decades, most researchers have agreed that these plaques and tangles are the key malefactors of dementia, and that if you could clear them from the brains of patients, you would halt or reverse illness. Researchers have been especially focused on finding a drug that could erase amyloid plaques, and we now have dozens of compounds that do that in mice.

But this approach has led to failure in humans. Even when drugs can clear the plaques in patients' brains, the disease continues to wreak damage.

Now some scientists believe that the focus on amyloid plaques might have been a mistake. Instead of looking at what goes wrong, they're trying to understand what goes right.

Changiz Geula, a professor of neuroscience at Northwestern University, has been studying brain tissue collected from people who died at age 90 or older. He found that some people who die with sharp minds have brains that are clogged with the gunk associated with Alzheimer's pathology. That means it's possible to have an "Alzheimer's brain" but no dementia. Dr. Geula believes that in cases like this, some actor in the brain — call it the opposite of Alzheimer's — is protecting neurons from damage. We still don't know what it is.

One candidate might be the astrocytes, cells that support the neurons and synapses, keeping them healthy even in the presence of plaques and tangles. In a 2017 paper in Nature, Stanford University researchers described how these usually peaceable cells can flip into a "killer mode," becoming assassins that spew out toxins and destroy the very cells they once nursed.

According to Shane Liddelow, one of the authors of the paper, this Jekyll-and-Hyde personality of the astrocytes likely developed thousands of years ago to fend off the infections that invaded the brains of our ancestors. At the first sign of trouble, the astrocytes go on the attack, destroying everything in their path — including sometimes healthy brain tissue. Neurons can become "innocent bystanders in this protective killing effort," Dr. Liddelow explained.

Nowadays, since most of us live in more sterile environments, this army in our brain is no longer busy fighting pathogens, and so it responds instead — often far too vigorously — to the amyloid plaques and tangles that are a part of normal aging.

"Ten years ago, very few scientists were looking at whether the immune system was related to Alzheimer's, but that question has just exploded," Dr. Liddelow said. "At every scientific meeting I'm at, everyone's talking about this question: Why are some people with lots of amyloid plaques — the people who, according to our models, should get Alzheimer's — protected from this runaway immune response? I think the answer will come from looking at immune cells of humans around the world living in different environments."

I asked Dr. Liddelow whether he was familiar with the Tsimane research. He admitted that he was not — the field of evolutionary biology is distant from his own. But he said the hypothesis that the ApoE4 gene evolved to protect our brains from the effects of parasitic infection made perfect sense. "That's absolutely in line with what we found. For our ancestors, an ApoE4 gene could have been beneficial," Dr. Liddelow said, in part because it would have helped the astrocytes go on the attack.

Dr. Liddelow, who just took a job as assistant professor at New York University, is now setting up his own lab to test out that theory. He believes that this new focus will lead to "a rapid production of effective treatments."

Dr. Trumble has hopes that his work will eventually lead to treatments as well. These days cancer scientists are brewing up designer viruses that help the body attack tumors. Why not designer parasites?

Soon after I first interviewed Dr. Trumble, he mailed some of his own saliva to a testing service to find out whether he had the ApoE4 genotype. Recently he received an answer: He carries one copy of the ApoE4 gene. For most Americans, that would mean an elevated risk of Alzheimer's disease. Of course, Dr. Trumble — who still spends months each year sleeping in a tent, eating wild meat and drinking river water — is no ordinary American.

I asked whether he thought his past infections had inoculated him against damage in his brain.

"I don't know," he said. "I'm definitely not going to run out and infect myself with more parasites, since the science isn't there yet" to show that these infections could be used as a therapeutic. "I definitely don't want people to read this and go out and try to infect themselves," he added. "Parasites can be very unpleasant or dangerous in their own right."

But, he said, "I certainly hope, before I get to age 80, we are able to figure out the mechanism" behind a pathogenic therapy.

Perhaps that would mean a drug for people who carry the ApoE4 gene, one that would mimic the effects of a parasite without incurring the damage of an infection — a kind of muzzle for the brain's immune system that would keep cells like the astrocytes from attacking healthy neurons.

Still, Dr. Trumble and the rest of the research team will need to gather more data before they can answer even the most basic questions: What is the rate of dementia in the Tsimane population? Are certain parasites more beneficial to the brain while others are harmful? And which humans are the most likely to receive a cognitive benefit from infection?

If the Tsimane do hold the keys to a cure, Dr. Trumble and his colleagues have no time to waste. "We have researchers in the field right now collecting data," he told me. "They're way upriver," in a settlement far off the grid. Yet Dr. Trumble gets frequent updates: He uses Skype to call into the Bolivian field office, where a radio relays crackly messages from his colleagues in the jungle. This jerry-built system has sped up the research process, but it also presages a time in which the Tsimane Project's mission will need to change.

Cellphones, canned food and other artifacts of modern life are seeping into the Tsimane communities. "This may be our last chance to understand whether chronic conditions of aging like Alzheimer's and cardiovascular disease have always impacted humanity, or whether they're connected with industrialization," Dr. Trumble said.

The Tsimane, he fears, are becoming weird like us.