Does modern society make people more susceptible to dementia as they age?

Why does a genetic mutation that is considered to be bad not be eliminated by natural selection, but instead persist in the human population?

Maybe it’s because it had a positive effect on humans who lived in the thousands of years before industrialization. We live in a completely different environment.

This article is authorized to be excerpted from Chapter 19 of "Borrowed Time" (Shanghai Education Press).

By Sue Armstrong

Translation | Chen Youxun

"My own feeling is, well, maybe half of Alzheimer's is environmental," says Caleb "Tucker" Finch, a professor of neuroscience at the University of Southern California. He is a doyen in the field of neurobiology of aging. And yes, he is a true pioneer in this regard. Finch has spent much of his career at the university. When he first started his research in 1965, he told me, as we sat together at lunch on a college campus, it was a relatively unknown area.

In 1959, as an undergraduate at Yale, Finch was considering entering the emerging field of developmental biology, which held an exciting future. One of his mentors at Yale, microbiologist Carl Woese, was a remarkable figure who had discovered a group of microorganisms called archaea that would revolutionize our understanding of the tree of life. The other end of the tree of life might present us with even greater challenges, this mentor suggested. “His advice to me was, if you really want to start over in a new field, why not consider studying aging?” Finch recalled.

“As a graduate student, I ended up writing my dissertation on aging, and I felt that the brain played a major role in that… In 1965, when I had written the outline of my dissertation, I had made my career choice—I decided to make this my life’s work.” Nothing since has swayed Finch’s resolve, not even the dismissive comments of the famous virologist Peyton Rous, who you may remember from the previous chapter as the man who threw cold water on Leonard Hayflick’s groundbreaking discovery that cells have a limited lifespan during division. When Finch spoke publicly about his research on the aging brain during his doctoral studies, he remembers Rous suggesting that he was wasting his time, since everyone knew that aging only caused vascular disease and cancer.

Now in his late 80s, Finch is tall, thin, slightly stooped, bald, and has a thick gray beard, but he has a quick mind and a curiosity about everything around him. A former graduate student described him in a profile of the scholar for Science magazine: "He looks like a god who has just come down from the Appalachian Mountains last week." This last comment is very relevant, because Finch is a violinist in his spare time and was a member of the Iron Mountain String Band, which he founded in 1963 with another friend, Eric Davidson, who is also a developmental biologist. He learned trumpet in elementary school and mastered how to play the traditional Appalachian fiddle by self-study at the age of 22.

Before the two scientists met, Davidson was in graduate school in New York collecting traditional music from North Carolina and southwestern Virginia for the Smithsonian Library of Congress. Finch joined him, spending a week or so each year out collecting music and transcribing it on their heavy old recording equipment. "You might visit a small town and walk into the local barbershop or the local hardware store and say, 'Who here plays the old-fashioned fiddle or banjo?' Then you'd go out and visit them in their homes and hear them play and record them," Finch recalls. "Our band was based on that music, so it was pre-bluegrass, a traditional Southern Appalachian string band." Finch laughs as he recalls the days under the Morton Bay fig tree in the campus cafe, where few people knew what they were doing on a daily basis. As he speaks, he's already finished a plate of burgers and fries.

What distinguishes Finch as a scientist is the breadth of his research. "What I did was to delineate a new area that few of my peers or colleagues in the field of biomedical gerontology had noticed, which was the environmental factors that contribute to aging, which, in my opinion, are far more important to humans than genetic variation," he explains. He believes that the impact of the environment on aging has been largely ignored "because it is difficult to study. You have to have a completely different set of theoretical assumptions and ways of thinking that cannot be derived from the traditional reductionism used in biochemistry and molecular biology. I think traditional reductionism is a good operating strategy for these problems, but the phenomenon of aging is a cutting-edge research area."

Finch's own training was also very different from the average person. As an undergraduate at Yale, he was able to work as a lab assistant in the newly established Department of Biophysics. "There was a group of brilliant physicists who went into biology and asked questions that no one else was asking," he recalls. "That's where I got my start. I was fortunate to have some great mentors early in my career who taught me not to be afraid to ask questions that upset people," he says. "Their attitude was 'If it hasn't been done before, don't worry, it doesn't mean it's not worth doing...leave those papers behind...let's take a broader view of what's going on in life that makes it behave differently than in physics.' That was my training."

What interests Finch now is how the diseases of aging have changed over the past 200 years as humans have lived longer. In particular, he wants to know whether our modern environment exacerbates age-related diseases that may have been rare in pre-industrial times. In an interdisciplinary collaboration with a group of anthropologists and biomedical scientists, he has been studying the Tsimane people of the Bolivian Amazon. Until recently, these people hunted, gathered, fished, and farmed as they had in the past, without access to modern medicine or other conveniences. "They have constant inflammation. They have parasites. They have tuberculosis and they get sick a lot because of the hard work they do every day," Finch says. "You would think that since inflammation drives so many diseases, they might be prone to heart disease, but that's not the case."

Over the years, the team's cardiologists have performed CT scans and electrocardiograms on hundreds of Tsimane participants in the long-running Tsimane Health and Life History Project. They found that arterial calcification occurs much later in the Tsimane than in other people living in modern society, so that the vascular age of an 80-year-old Tsimane is generally about the same as that of an American in his 50s. "We also did brain imaging scans on them, and found that their rate of gray matter loss during aging is at least 50% slower than that of people living in North America and Europe," Finch said.

Over the years, a wealth of data on Amazonian cognitive function has also been collected, which is beginning to reveal some intriguing evidence about the interaction between genes and environment. APOE e4 is known to be the single highest risk factor for Alzheimer’s disease in industrialized countries, but in the Tsimane people, who are frequently infected with parasites, the gene seems to offer protection for their brains. What’s more, the gene seems to start working at a very early age: Tsimane children who carry a copy of the APOE e4 gene are generally smarter than those who don’t. This mirrors findings from studies of children in poor neighborhoods in Mexico City and Brazil: those children were particularly susceptible to infection, but those with the e4 variant seemed to have better cognitive abilities.

Yet the relationship between bacteria and genes, and how it affects the brain, is complex. Uncontrolled parasitic infections can damage the brain on their own, so the Tsimane, young and old, would have been vulnerable if they didn’t carry the protective APOE e4 variant. In the few individuals who somehow escaped parasite infection but carried the APOE e4 gene, the variant behaved as it does today—increasing the risk of mental decline. Finch says the findings offer a plausible explanation for why a gene variant considered bad has persisted in human populations without being eliminated by natural selection: It had a positive effect on humans who lived thousands of years before industrialization because they were in close contact with a large number of invasive organisms. They also offer clues to why the effects of APOE e4, mentioned above, vary among different ethnic groups.

Ram Rao, a neurologist who studies APOE at the Buck Institute, looks back to the origins of the Neanderthals. He agrees with Finch's explanation for why the harmful e4 variant persists in humans. "It's a great story," he says, enthusiastically. "APOE causes inflammation. The fact is that the Neanderthal was always looking for food. They had no shoes, no socks, no slippers. The Neanderthal was walking on bare ground, sometimes climbing trees. He had to walk for miles to find a good kill and bring it home. In the midst of all this, they would get infections, bleed [from cuts and scrapes]. And then, if they didn't get the kill, they would have to go hungry for a long time. All of this required them to stay active, and APOE helped with that. So APOE was a boon to them...it prevented the spread of infection in the body."

"Now that same caveman gets all the health care he needs, lives past 50, starts wearing shoes and pants and shirts and eating all kinds of bad food, and the APOE e4 in his body doesn't know what to do. It gets confused. The good and evil gene now starts to show its evil side. The same APOE e4 becomes the culprit for the inflammation that was originally a way for the body to maintain health, but now, as we age, causes the body to function abnormally."

But what is the relationship between genes and bacteria at a cellular level deep in the Amazonian brain? Based on a careful examination of reams of data from field trips into the jungle, the researchers theorize that APOE e4 protects the Tsimane through two possible mechanisms: by neutralizing and eliminating parasites from their bodies, or by altering cholesterol metabolism in the brain to mitigate the effects of parasitic infections. But coming up with a theory is only a start; the big challenge is to confirm or refute it and explain in detail how it works.

This research project, conducted in pre-industrial populations, could provide tantalizing evidence of the role of the environment in how our brains age. But where are the environmental threats, given all the pest and germ prevention measures in modern society? But Finch points out that there are many potential threats in modern society, and his main focus is on air pollution. We are talking about ultrafine particles with a diameter of no more than 2.5 microns (about 30 times smaller than the diameter of a human hair). They are called PM2.5 (short for particulate matter 2.5), and they are produced by the burning of fossil fuels and are mainly emitted into the atmosphere through power plants and car exhaust pipes. They contain many harmful substances, such as sulfates, nitrates, hydrocarbons and heavy metals, including lead, nickel, mercury... After a period of research, there is increasing evidence that air pollution can damage the brain.

In the early 2000s, for example, after the World Health Organization identified Mexico City as one of the worst places on Earth for smog, researchers in the city began monitoring the effects of air pollution on dogs, who live in the same conditions as humans, to understand how it might harm city dwellers. According to Dr Lilian Calderón-Garcidueñas, who led the research team, residents in Mexico City reported signs of abnormal behavior in their dogs, such as changes in sleeping patterns and incessant barking. Some dog owners told researchers that their dogs sometimes seemed unrecognizable to their owners. The researchers closely monitored the dogs and examined the brains of the deceased dogs, finding accumulations of amyloid beta, plaques and other pathology similar to Alzheimer's disease in humans, including dead neurons, the researchers reported in 2003 in the journal Toxicological Pathology. In the final paragraph, they write: “These findings in canines are of sufficient magnitude and clinical relevance to raise concerns that similar pathologies may be accelerated in humans living in large urban areas or exposed to high levels of particulate matter from wildfires, natural disasters, or warfare events. Neurodegenerative diseases such as Alzheimer’s disease may be linked to air pollution.”

Recent studies in the United States and elsewhere have suggested a link between mental decline in older adults and exposure to fine particle pollution. Finch and his colleagues have been working on a project that combines human epidemiological studies with experiments in mice and cell cultures in an effort to amass a large body of indirect evidence to prove a cause-and-effect relationship. They set out to answer three broad questions: Are older adults at increased risk for dementia if they live in places with high concentrations of PM2.5 in the air? Are those with the APOE e4 gene more sensitive to the effects of these pollutants? Can these findings from humans be replicated in mice with the APOE gene under controlled conditions in the laboratory? If the answers to all three questions are yes, they believe, “it will help shed light on the underlying mechanisms at work in the human brain.”

For the human portion of the project, Finch and epidemiologist Jiu-Chiuan Chen, a colleague at USC, teamed up with researchers at Wake Forest University School of Medicine in North Carolina as they conducted the Women's Health Initiative Memory Study (WHIMS). The researchers drew from a database of 3,647 women who had been enrolled in the study since the late 1990s, were between 65 and 79 years old at the time of recruitment, and showed no signs of intellectual disability. The women came from across the United States. For all of the participants, WHIMS had detailed information about them, including their physical characteristics, clinical history, lifestyle, behavior, and genetic characteristics, which was particularly important because it could reveal their APOE status. Using this rich resource and air quality data collected from the U.S. Environmental Protection Agency, the USC team built a mathematical model that allowed them to assess daily outdoor PM2.5 levels in different locations over the 10 years leading up to 2010 to gauge whether the women in the study were likely to have been exposed to these harmful pollutants.

When all the mysteries were solved, the researchers found that women who lived in places where air pollution levels regularly exceeded national safety standards had much faster mental declines and were nearly twice as likely to develop dementia, including Alzheimer's disease, as those who lived in less polluted environments. In addition, women with the APOE e4 gene had a two to three times higher risk of the disease than women with other variants of the gene. "If our findings apply to the general population, then fine particulate pollution in the ambient air could be a contributing factor to one in five cases of dementia," Finch commented.

Back in the lab, Finch and his team exposed mice engineered to carry the human APOE gene variant to carefully controlled doses of ultrafine pollutants called PM2.5, collected from motor vehicle traffic that crosses USC’s campus roads. They worked on the project in collaboration with Constantinos Sioutas of the USC School of Engineering, who designed a complex contraption of pipes and filters that captures car exhaust and stores it in a suspension. They could then re-aerosolize the suspension to expose mice to the pollution in the lab. “It’s better than putting mice in cages near a highway, right?” Finch said.

Half of the mice were exposed to exhaust fumes for an average of five hours a day, three days a week, for 15 weeks. The other half, a control group, were allowed to breathe clean air. Then they killed all the mice and examined and compared their brains. The researchers found a lot of inflammation caused by microglia, the brain's clean-up cells in the immune system, which are activated to deal with invading particles. They also found that the microglia released high levels of an inflammatory molecule called TNF-α (tumor necrosis factor), which is often elevated in the brains of people with Alzheimer's disease and causes memory loss. Like Lillian Calderón-Garcidueñas's study of dogs in Mexico City, Finch's team found excessive accumulation of beta amyloid in the brains of mice exposed to pollution. To analyze it more accurately at the molecular level, they cultured cells from the brain's immune system in laboratory dishes and exposed them to exhaust fumes.

“We now know that particulate matter from fossil fuels enters the brain directly through the nose and can also enter the body’s circulation through the lungs, ultimately causing an inflammatory response that increases our risk of Alzheimer’s disease and accelerates the disease process itself,” Finch said in a USC news release. In addition, he noted that through laboratory studies on genetically modified mice, “we were able to clearly show that exposure to air pollution increases levels of amyloid in the brain, and this was even more pronounced in mice carrying the human Alzheimer’s risk factor APOE e4.”

Our brains are protected from microbes and other harmful substances entering the bloodstream by something called the blood-brain barrier. The blood-brain barrier is a semi-permeable layer of endothelial cells that tightly wraps around the walls of brain blood vessels. But we know, Finch said, that in people with the APOE e4 gene variant, the blood-brain barrier is more permeable than normal, allowing the ultrafine particles they breathe to enter the brain more often. Ultrafine particles that enter the brain directly through the nose travel along the olfactory nerve, which gives us our sense of smell and connects to the hippocampus, where memories are stored.

Since the ability to smell immediately, and thus to get information from the surrounding environment, has been crucial to the survival of the species, the olfactory nerves, which start in the nose, have been the only natural flaw in the blood-brain barrier. Dogs have a much more acute sense of smell than we do, but Calderón-Garcidueñas found in his study in Mexico City that they have extensive damage to the olfactory system from the nose to the brain. Interestingly, the inability to smell certain odors has recently been found to be an early sign of Alzheimer's disease, and the main mechanism seems to be that the accumulation of beta-amyloid kills the olfactory nerve cells.

At USC, Finch was also very interested in how smoking affects air pollution, and this deserves a little background. Smoking has long been thought to increase the risk of cardiovascular disease and cancer. But until 2010, the relationship between smoking and dementia was controversial: some studies showed that smoking did increase the risk, while others found no effect, and some even said that the risk was actually reduced. Then in 2010, Janine Cataldo and her colleagues at the University of California, San Francisco, published a paper describing how they systematically analyzed the design, methods, and findings of 43 original international studies conducted between 1984 and 2009 to address this question. Notably, in an effort to minimize potential conflicts of interest in their results, they also looked at the funding and departmental affiliations of the scientists involved, something that, surprisingly, seemed to be ignored by the journals that published the reports. Anyone familiar with the tobacco industry’s efforts to discredit evidence that smoking causes cancer will not be surprised by what Cataldo and her colleagues found: tobacco companies’ influence can be seen in all the evidence on Alzheimer’s disease.

Finding out which research projects and scientists were supported by tobacco companies thus became a major detective exercise. It involved a sweeping search of a trove of internal documents kept in traditional tobacco repositories, which had been kept secret until they were forced to open by lawsuits filed by customers angry about personal damage and death caused by smoking. The researchers found that of the 43 studies included in their meta-analysis[1], 11 were conducted by scientists with ties to Big Tobacco, and only three of those disclosed the existence of such ties. None of the 11 studies found an increased risk of Alzheimer’s among smokers; in fact, eight of them even showed a reduced risk, while the others found no significant effect. Yet, after adjusting for the biases inherent in the tobacco industry-backed studies and other factors, such as study design, Cataldo and her team concluded that “smoking does not protect against Alzheimer’s disease.” In fact, the data they had showed that “smoking is a substantial and important risk factor for Alzheimer’s disease.”

So what do these statistics mean for a smoker? That obviously depends on how many cigarettes a person smokes a day, how long he or she has smoked, their genetic background, and many other variables. However, a 2014 fact sheet from the World Health Organization cites studies from around the world that estimate that smoking increases the risk of the disease by 59% to 79%. In addition, the WHO estimates that about 14% of Alzheimer's cases worldwide are "likely to be attributed" to smoking.

Finch says tobacco has many different mechanisms by which it can increase or accelerate a person's risk of cardiovascular disease and cancer. But what about the brain? He is exploring the cross-talk between smoking and air pollution, studying to what extent they work by the same mechanisms and whether the two air pollution states work together to add to a person's risk of Alzheimer's disease. From the evidence available so far, he says, "I conclude that there is another harm in this combination that has not been widely appreciated, and we don't have a ready mechanism to explain it."

"From another perspective... in some countries with high population quality, the number of smokers is being compressed to 10% to 15% of the adult population. However, for every adult smoker, most of them live with other people, and the proportion of households exposed to secondhand smoke in all households may be close to 40% to 50%. Therefore, even if a person does not smoke at home (their number accounts for 1/3 of the world's population), if they are unfortunate enough to live in a high-pollution area where smoking occurs, they will also be affected."

In modern society, Finch says, all forms of air pollution — whether it’s smoking, smog or anything involving the inhalation of nanoscale particles — have become a new frontier in research to determine people’s risk of developing Alzheimer’s. He’s asking some big questions in his research and is eager to find out. For example, does air pollution trigger or simply accelerate the development of Alzheimer’s? Do his broad findings on women apply to men as well?

Dementia is now the most feared disease of aging, largely because it remains so pervasive, so relentless, and so devastating to the lives of its sufferers. But how has the treatment landscape evolved in the more than a century since August Deter was taken to see a psychiatrist? “I think there’s a tremendous opportunity here to significantly reduce the burden of dementia worldwide,” says Dale Bredesen, a practicing physician and neurologist who was the Buck Institute’s founding director in 1999.

Why is Bridson so optimistic? In the next few chapters, I'll explore the prospects for treating Alzheimer's disease today. We'll also look at how other aspects of aging, from shortened telomeres, senescent cells, and a dysfunctional immune system to the dual nature of certain genes and the damaging effects of free radicals, hold up in practice. And what else will we need to do to slow down or dramatically improve the aging process in humans?

Notes

[1] In statistics, meta-analysis refers to a statistical method that integrates the results of multiple studies. In terms of usage, it is a new method of literature review. The traditional method of literature review is narrative, in which the author selects the previous studies that he or she thinks are important. When the conclusions of the studies conflict, the author decides which conclusion is more valuable. - Editor's note