Hey team,
We’ve spent a lot of time on this newsletter talking about how to optimize your brain, how to sleep better, and how to train your nervous system for peak performance. But today, we need to talk about the elephant in the room.
We need to talk about APOE4.
If you’ve ever taken a 23andMe test, or run your DNA through a health panel, you know exactly what I’m talking about. APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease. In populations of European ancestry, about 25% of people carry one copy. But roughly 2% to 3% of the population carries two copies—meaning they inherited the gene from both their mother and their father.
These are the APOE4/4 homozygotes.
For decades, the medical establishment has treated an APOE4/4 genotype like a slow-moving death sentence. Patients are told they have an eight to ten times higher risk of developing Alzheimer’s in prospective studies. They are told the disease will likely strike them significantly earlier than everyone else. And worst of all, they are told there is nothing they can do about it.
But the science has shifted dramatically in the last few months.
If you carry the APOE4 gene—or if someone you love carries it—what I am about to share with you changes everything.
The Weekly Task
Before we get into the science, here is your task for the week: Find out your APOE status.
If you have raw DNA data from any commercial testing service, you can run it through a secure health analysis tool to find out your APOE genotype. Knowledge is power. You cannot out-train or out-sleep a biological mechanism you don’t understand. Find out where you stand.
The Decades-Old Mistake
For years, scientists believed that the APOE4 gene was dangerous because it was “weak.”
The theory was that the protein it produced (ApoE4) was just really bad at its job. Its job is to shuttle fatty substances around the brain, clearing out debris and keeping neurons healthy. Researchers assumed ApoE4 was a lazy garbage truck driver, letting amyloid plaque pile up in the streets until the brain eventually succumbed to Alzheimer’s.
Because of this theory, the entire pharmaceutical industry focused on building drugs that clear amyloid plaque out of the brain. You’ve probably heard of them: Leqembi and Kisunla.
But here is the devastating truth that emerged in early 2026: Those drugs carry a significantly elevated risk of ARIA (brain swelling and micro-bleeding) in APOE4/4 carriers.
While both drugs are FDA-approved for APOE4 carriers, they require enhanced monitoring. The very drugs designed to save Alzheimer’s patients present the highest risk profile for the people who need them most.
The APOE4/4 community was left behind.
But then, a team of researchers at the Gladstone Institutes in San Francisco looked closer at the brains of young mice carrying the APOE4 gene. They weren’t looking at old brains filled with plaque. They were looking at young, healthy brains with perfectly normal memory and learning capabilities.
And they found something that completely shattered our understanding of the disease.
The APOE4 gene wasn’t just failing to clear garbage. It was actively rewiring the brain’s circuitry decades before the first symptom ever appeared. It was shrinking neurons. It was making them hyperactive. It was burning the brain out from the inside.
But the researchers didn’t stop there. They identified the exact protein causing this damage. And then, in a breakthrough published just weeks ago in Nature Aging, they did something that was supposed to be impossible.
They reversed it.