For decades, researchers believed that Alzheimer’s was driven by the accumulation of harmful proteins in the brain called beta-amyloid. This has come to be known as the “amyloid hypothesis,” and it’s still the prevailing theory in the field. But it’s been subject to scrutiny in recent years, as drugs targeting the proteins have failed to yield anything more than mild improvement in patients, leading some experts to continue searching for another suspect behind this form of cognitive decline.
One potential culprit is microglia. These cells, which account for just 10 percent of the brain, are often referred to as “trash collectors,” since they clear the organ of damaged tissue and toxins. But new research suggests microglia cells may play a much more important role than we’ve given them credit for, with the power to either protect us from waning cognition or drive the development of a range of neurodegenerative diseases.
That’s the focus of Brain Defenders, an upcoming book by neurologist David Perlmutter, MD. In it, he explains how microglia can tip the balance in the brain — and what steps we can take to keep them functioning properly.
Like many of his books (this is Dr. Perlmutter’s eighth), Brain Defenders makes some bold, sometimes controversial claims that challenge mainstream medical opinion. Its point is to provoke, he tells Katie Couric Media's Body and Soul newsletter, and to jolt the millions of Americans projected to develop Alzheimer’s or dementia over the next decade to act immediately.
“You’ve got the tools right now to change the trajectory of the brain as you age,” he tells us. “You are the architect of your brain’s destiny.”
We spoke to him about the powerful lifestyle changes he recommends and the promising new research that he believes could be the key to solving the Alzheimer’s puzzle.
First off, what are microglia — and what’s the theory behind how they can either protect or harm the brain?
Dr. David Perlmutter: Microglia are part of the brain’s immune system, and they’re also involved in maintenance — making sure neurons, synapses, and the blood-brain barrier are all working properly. But they also have another important characteristic: They can shift from being supportive — a form called M2, in which they act as brain defenders — to being destructive, a form called M1. In this state, they can cause chronic inflammation in the brain and kill brain cells. This shift is a central event across a spectrum of neurodegenerative conditions, like Alzheimer’s, ALS, and Parkinson’s.
What leads microglia to malfunction?
Issues like elevated blood sugar, insulin resistance, excess visceral body fat. Microglia are very sensitive to these metabolic changes. Things like changes in the gut bacteria — brought on by an inappropriate diet high in ultraprocessed foods or taking certain acid-blocking drugs — can ultimately increase inflammation and trigger these changes in the microglia, too.
In Brain Defenders, you argue that the buildup of beta-amyloid in the brain, which is considered a hallmark of Alzheimer’s, isn’t what’s driving the disease. Why is that?
Beta-amyloid plaque is not the cause of Alzheimer’s, period. If it were, one would assume that getting rid of it would resolve the issue, but that hasn’t been the case. A recent analysis, called the Cochrane Review, looked at data from 17 clinical trials with more than 20,000 participants and determined that the drugs do reduce the amyloid burden, but they have virtually no effect on changing the downward spiral of these patients. Plus, there are plenty of Alzheimer’s patients who don’t have much amyloid plaque in their brains at all, yet they die of the disease. And there are plenty of individuals with lots of the substance in their brains who are cognitively intact.
What are some things people can do to protect their “brain defenders”?
The science supports basic things like exercise, a lower carbohydrate diet, restorative sleep, and stress reduction. These are all things that people know about, but they really are the keys to the kingdom. And the foundational point I make in the book is that these changes to metabolism that presage cognitive decline happen in our thirties and forties — well before most people show any symptoms. So you can act now, with these tools, to redirect the ship as it relates to your cognitive future.
When it comes to modifying your diet, what do you recommend?
The Mediterranean diet or the MIND diet. They’re supportive of the brain because they keep blood sugar regulated and they nurture the gut microbiome by virtue of being high in fiber, which reduces inflammation. You also want to incorporate lots of color into your diet, with vibrant fruits and vegetables that are high in polyphenols, which reduce free radical stress and shore up the lining of the gut.
What’s the biggest thing people can do today to protect their brains?
I think the one big thing to embrace is that you have the ability to change your brain’s destiny by making lifestyle modifications like we’ve discussed. Other than that, elevated blood sugar is the clearest and most present danger to the brain that there is. And I also believe that it’s not good enough to be in what’s accepted as the “normal range,” or just low enough so you’re not considered diabetic. You want to optimize those numbers.
Are there new therapies being developed that target microglia?
There’s research looking into how to keep microglia in their M2 supportive configurations. One company called Vigil Neuroscience is focusing on the TREM2 receptor, which is on the surface of microglia, and has been shown to stimulate this protective response. We’re seeing experimentation around microglial transplantation and innovative research out of MIT looking at how exposure to light and sound at certain frequencies can boost microglia and improve Alzheimer’s symptoms.
This is the future of neurodegenerative conditions, and we’re not talking about the distant future. I believe we’ll see incredible developments in the near term that will give us some powerful tools to treat neurodegenerative conditions — well beyond targeting beta-amyloid.
This interview has been edited and condensed for clarity.
