How far we’ve come! When Jacques Miller began his quest to understand the thymus, the leading causes of death were pneumonia and flu, followed by tuberculosis. Much farther down the list were heart disease and cancer. Thanks to science, we chipped away at these diseases that had decimated generations and made of them low-hanging fruit.
The key had been to understand and bolster the immune system, do it with antibiotics, vaccines, and other medicines and surgical procedures that the system itself could not accomplish entirely on its own.
But like death and taxes, some things just can’t be put off indefinitely. One is wasting brain.
As science helped us evade the imminence of the deadliest threats of the past, a potent new danger rose on the list of mortal causes: neurodegeneration. Alzheimer’s, Parkinson’s, sometimes Lou Gehrig’s disease, in which the motor function of the brain disintegrates.
Worldwide, 47 million people had Alzheimer’s in 2017, according to the Alzheimer’s Association, a figure expected to grow to 74 million by 2030. In the United States, there are more than 5 million, which means a disproportionate share of sufferers are here, nearly double the rate here as around the world. That’s likely because we have longer life-spans. Life expectancy had grown to nearly seventy-nine years, up from around seventy-five in the late 1980s (the opioid crisis has had a powerful negative impact here, and obesity was worsening it too). Alzheimer’s was the sixth leading cause of death in the United States. It’s part of the immune story.
This is what happens when you live longer. Eventually, your brain fails, even as your body goes on.
It’s terrifying up close, as a growing number of people experience. Our intimate window comes not from Jason or Bob or Linda and Merredith, but from two of the scientists I introduced earlier, Jan Kiecolt-Glaser and Ron Glaser. They were the scholars at Ohio State University who had spent their lives studying the relationship between health and stress. Their own relationship with stress turned highly personal in June of 2011.
In the months just prior, Ron had become increasingly nervous when giving lectures. He made sure every idea that he wanted to speak about was on one of his PowerPoint slides. That way he wouldn’t forget what he was talking about.
For years, Jan said, “he thought his memory was getting worse.”
Ron was born in 1939. He was seventy-two. He looked physically fit at five-eleven, with silver hair and a touch of a belly. Around him, his colleagues and friends didn’t notice anything wrong. His mother had had Alzheimer’s, so he knew he might have a genetic predisposition to it.
He and Jan secured an appointment with a neurologist.
“When he wanted to make the appointment,” Jan said, “I was scared to death.”
Jan and Ron sat across from the neurologist, who was the head of the memory disorders clinic at Ohio State. Prior to the visit, Ron had completed a handful of tests, including a drawing test in which he had been shown pictures he was supposed to copy. It should’ve been simple, particularly since Ron had been an art minor in college.
When the couple met with the neurologist, they were shown Ron’s drawings. “It was incredibly bad,” Jan said. One of the images was an attempt at a three-dimensional box. “It was quite clear he could not copy the picture.”
The neurologist told the couple “all the things they had ruled out,” like a brain tumor. “You’re doing well overall,” the neurologist told them, “but there are some issues.” He gave them a diagnosis of mild cognitive impairment.
But Jan could read upside down from the other side of the desk what the neurologist had written: probably early Alzheimer’s.
Jan went home and read the research on mild cognitive impairment. She was the patient now, or the patient’s wife, not the distant reader of her own work. She didn’t like what she learned. Twelve percent of people like Ron would, on average, progress to full-blown Alzheimer’s.
Ron seemed to be defying that. Through each of the next few years, he kept functioning. “Everybody saw him as the person they’d always seen him as,” Jan said.
“Then, in 2014, he fell off a cliff.”
He’d gone to the neurologist regularly and gotten tests of cognition that showed him dropping about 3 points per year on the scale they were using. But around 2014, he went from a score of 24 to 5 over the course of about a year. What is likely to have happened is that he had been so high functioning during his life that he was able to go through the motions of his life, in effect masking the cognitive decay.
When the mask came off, it was ugly. He couldn’t reliably answer the phone or use a microwave, brush his teeth. He once put toothpaste on a comb. “It was really fast,” Jan said, “and really awful.”
This is an increasingly common experience. But what does it have to do with the immune system?
Up until this point, as I’ve used the metaphor of life’s festival being protected by our immune system, I’ve essentially lumped together the entire human body.
In reality, when it comes to the immune system, one part of the body stands largely apart. That’s the brain. It has proven more challenging to unpack than any other part of our elegant defense. One simple reason for this is that it’s not easy to get a slice of it or to peer into it, certainly in real time.
The immune system and the brain, each by itself, are among the most complicated organic systems in the world, so dissecting their relationship has meant understanding each alone as well as their coordinated efforts.
There was a period when it wasn’t even clear whether there was an immune system in the brain, at least like the one in the body. Part of the issue was a bottleneck known as the blood-brain barrier. This is a network of blood vessels that keeps close control over what flows between the brain and body, and that keeps many of the chemical reactions and other functions of the body from leaking into the brain. This has the profound and crucial function of keeping infection out of the brain. It’s hard for molecules to get in and out. (Instead, the brain corresponds with the body through nerves that carry the electrical signals that control motor functions.)
But the immune system cells, so free-roaming in the body, are generally not crossing back and forth into the brain.
“The brain was thought to be immune privileged,” said Dr. Ben Barres, a pioneering researcher in the field of Alzheimer’s and, ultimately, in its relationship to the brain’s own immune functions. “The brain has this special barrier. The immune system is not just leaking into the brain.”
The brain has its own thing going on.
Brain 101: There are cells called neurons, which communicate through synapses. These connections have an almost magical power to create networks that allow the mind and body to work together. The result is a veritable neural symphony of chemical reactions executed in perfect unison. Think, for instance, about all that has to go right when someone walks or talks, let alone does a more complex task, like hitting a tennis serve or playing a piano or solving a math problem while writing the answer down with a pencil.
Graduate-level neuroscience: These neurons aren’t the lion’s share of the brain. A lot of the volume of the brain is consumed by a set of cells called the glia—comprising 80 percent of the brain, Dr. Barres told me. Broadly, glia are non-neuronal cells. These glia are central to the immune function of the brain. The glia come in three flavors: astrocytes, oligodendrocytes, and microglia.
As we live longer, these cells are going to be crucial in how we understand dementia and how we deal with it. What follows is a primer on the cells, their roles in the brain’s immune function and its relationship to aging.
Astrocytes look like big stars. They play a critical role in helping the synapses communicate by enveloping them—a single astrocyte can envelop millions. “Astrocytes are orchestrators,” I was told by a Stanford researcher, Dr. Vivianne Tawfik. Coordinators and organizers, packagers and bundlers. Crucially, the astrocytes also encase blood vessels, influencing blood flow. This helps dictate where and how much blood concentrates in the brain, with more active regions needing extra blood at any given moment, just like an active muscle receives added blood flow.
Oligodendrocytes help the neurons conduct faster signals. I think of them as speed amplifiers for your brain’s internal communications network, like a Wi-Fi booster that brings the signal farther faster.
Then there are microglia. “They are the immune cells of the central nervous system,” Dr. Tawfik explained.
Like the body’s immune system, which originated to no small extent in the thymus, the brain’s immune system also has origins in an organ long thought to be vestigial.
When a child is conceived, one of the first organs to form is the yolk sac. It eventually becomes round and grows to an average of 6 millimeters. It is a sort of food filter, with nutrition coming from the mother through the yolk sac and into the tiny forming life.
But the yolk sac performs another essential function. It is there, scientists discovered, that precursors to microglia originate, and from there move on to populate the brain. Once in the developing brain, the microglia play a key role. As the brain develops and neurons mature and die, the microglia consume the refuse. Does this sound familiar? It should. It is like the work of monocytes. It is phagocytosis. The microglia are eating neurons that must be pruned, and possibly synapses too.
Scientists’ understanding of the role of the microglia and the astrocytes was embryonic in the mid-1990s, when Dr. Barres committed himself to trying to comprehend how this poorly understood system might be involved with neurodegeneration. Was our brain’s defense somehow causing Alzheimer’s?
Ben Barres was born on September 13, 1954. His given name was Barbara. He was born a girl, and from the earliest days, that felt wrong. “I realized from the time I was a few years old I was feeling like a boy,” he said. Not much to be done about that. Not then. There wasn’t even a language for it, so Barbara Barres stuffed down the feelings, wavered with suicidal ideations—“the typical transgender stuff you hear about”—and threw herself into a medical and science career turning stratospheric. She went from MIT to Dartmouth to Harvard and then Stanford. She became an expert on the brain.
In the mid-1990s, she read an article in the San Francisco Chronicle about a female-to-male activist in the region. She started to feel like she wasn’t alone, like there might be an answer.
Then Barbara found a lump in her left breast. It was cancer. Barbara needed a mastectomy. She visited a surgeon at Stanford, and when he explained what he was going to do, she said to him: “While you’re taking the left one off, take the right one off too.”
Dr. Barres became Ben, blessed with a terrific sense of humor, and these kinds of comments prompted him to burst out laughing. The surgeon, Dr. Barres said, “was the first one I ever told.”
The surgeon told his then-female patient that there was no health reason to take off her right breast.
“There’s no way you’re going to put those things back on me!” Dr. Barres told me he said, laughing. He’d go on to transition to becoming a man, and much later, he’d become something of an icon for the movement, even appearing on Charlie Rose to discuss it. With a new lease on life, having beat cancer and made peace with his identity, he committed himself to understanding the brain’s immune system. He became a world authority.
Over time, Dr. Barres defined an immune system network inside the brain that was analogous to, but largely distinct from, the one functioning inside the rest of the body. Just like the body’s defenses, the brain’s defenses can cause issues. One particular paper explored the relationship by focusing on how mice develop glaucoma, a condition that in aging humans causes eye pain and can lead to blindness.
The mouse paper focused on a molecule called C1q that is involved in the immune system in the brain. Inside the brain, C1q binds to things that do not appear to be self. If C1q binds to a foreign organism, it can lead to an immune response and the destruction of the foreign presence.
In the case of mice with glaucoma, Dr. Barres and his coauthors found an extraordinary relationship between these immune functions and the disease. When mice develop glaucoma, it triggers the microglia to begin eating synapses, including healthy synapses. It’s like the brain’s immune system is turning on itself.
I asked Dr. Barres the obvious question: Why?
“If I knew that,” he said, laughing, “I’d get a Nobel Prize.”
Over time, though, he developed several well-founded theories that do seek to answer the question of why the aging brain appears so vulnerable to degeneration, not just with glaucoma but Alzheimer’s and other conditions. One theory, Dr. Barres said, is that our brains wind up over the years with a lot of detritus—garbage—that needs to be eaten up. That spurs the microglia to eat synapses. The janitor starts doing its job, but then the janitor goes nuts and starts eating everything in sight. In the Festival of Life, the janitor is not just cleaning up but also taking cups and plates out of the hands of partygoers—booting out cells while the party lights are still on.
Dr. Barres postulated to me that evolution has allowed such a process to go forward because older human beings are less valuable to the species. “There’s nothing in evolution that would select for good brain health when you’re aging. You’re already through reproduction.”
You’ve passed on your genes. What good, then, is a healthy brain?
This is speculation. For now, the science of the immune system and the brain is still embryonic, much less developed than our understanding of our body’s elegant defense.
So for now, Alzheimer’s involves lots of coping, rather than solving.
For nearly two years, since late 2015, Ron had lived in a memory care unit. He’d dropped to 140 pounds from 180. Jan came every few days, bringing him candy, usually jellies, and sat down and put her arm around him. He didn’t recognize her. He usually didn’t look at her. Sometimes, he talked to things that don’t exist. He was hallucinating. He took antipsychotics.
“He’s pretty tame and easy compared to many people,” Jan said. Small comfort. “It’s like most of Ron has disappeared. There’s a shell that looks somewhat like him, and that’s about it.”
The circumstances have forced Jan to take very personally a lifetime of work about stress and health, namely her own health. “I go through spells,” she told me. “I’ll be okay and he’ll take another step downwards and I’ll get sad and depressed again.”
What Jan knows from her own research, and the research she follows closely, is to keep her stress low and her social activity up, all of this having an impact on her mood and health. She keeps up a daily meditation practice, usually twenty minutes in her office. She tries to eat well, meaning greens and beans, because she believes that junk food impacts the microbiome, which in turn interacts with her stress levels.
“The gut-brain axis and the immune system, it’s a very close involvement,” she says, sounding as much like a patient looking for answers as she did the eminent scholar. She draws from a recent report from the National Academy of Medicine that relates physical health to strong relationships, good diet, factors you can control: “things that your grandmother or mother told you that mattered—you need to eat better, you need to move—but they are the hardest things to do when you’re stressed.
“When we’re stressed we don’t want to reach for the greens and beans. A chocolate doughnut is really appealing. They may be briefly comforting, but they’re bad for the longer-term process.”
It also helps to cry, she says. She means we need to release stress. Otherwise the stress leads to inflammation, poor mood, fatigue, and heightened inflammation, and that can have lots of correlates. It can affect mood.
“Crying is beneficial,” she says. It’s an acknowledgement of who and where you are, an embrace of self at a given time and, as such, it helps the immune system by sparing it from having to deal with the repressed anxiety. Crying “is not fun. It’s painful. But you feel better in many cases thereafter, as opposed to eating the chocolate doughnut.”
These ideas are, as you’ll see shortly, lessons to live by.