When Bruce Yankner's team published their findings last August, his inbox stopped being his own.

Messages have been pouring in ever since, from people living with Alzheimer's and from the families who love them. All of them want to know the same thing: is this the breakthrough?

"I try to get back to everybody who contacts me," Yankner, a professor of genetics and neurology at Harvard Medical School, told the Harvard Gazette. "I try to provide hope."

There is, cautiously, reason for it.

A missing ingredient in the brain

Yankner's decade-long study, carried out at the Paul F. Glenn Center for the Biology of Aging, has uncovered something nobody knew was there: lithium, the same element used for decades to treat bipolar disorder, occurs naturally in the human brain — and appears to be quietly essential to keeping it healthy.

The team found that lithium helps maintain the normal function of every major type of brain cell. Crucially, they also found that lithium depletion is one of the earliest changes seen in Alzheimer's disease, a condition that affects more than 50 million people worldwide.

When the researchers reproduced that depletion in mice, the results were stark. The disease accelerated dramatically. Memory loss followed.

Why amyloid matters — and why some brains cope

The finding may also solve a puzzle that has bothered Alzheimer's researchers for years.

Some people die with brains "riddled with amyloid plaques" (the sticky protein clumps long associated with the disease) yet remain mentally sharp. Others, with similar levels of amyloid, are severely impaired. Why?

Yankner's team think they have part of the answer. Their work shows that amyloid plaques actively bind lithium, mopping it up and starving the brain of a metal it needs to function. People with higher baseline lithium levels may simply have more in reserve.

It is, in other words, not just how much amyloid you have — but how much lithium it has stolen.

A new compound designed to slip past the plaques

The most exciting part, for families waiting for treatments, is what came next.

Working with research associate Liviu Aron and postdoctoral fellows Ngian Zhen Kai and Chenxi Qiu, Yankner's lab developed a screening platform to test lithium compounds that could evade being captured by amyloid. One stood out: lithium orotate.

In mouse models, lithium orotate appeared to prevent and even reverse Alzheimer's pathology and memory loss. The animals' brains, in effect, got their lithium back.

It is a striking result. It is also, importantly, still a result in mice.

"Many people are waiting for this"

Yankner is careful, and he is firm, about what families should do with the news in the meantime.

When people ask whether they or their loved ones should start taking lithium supplements, he tells them to wait for clinical trials and to talk to their doctor. Lithium at therapeutic doses has well-known side effects, and lithium orotate as a treatment for Alzheimer's has not yet been tested in humans.

"People who have loved ones with Alzheimer's understandably have difficulty waiting for the results of clinical trials, which by their nature, take a long time," he said. "But our method of going from the laboratory to the clinical trial has been validated many times."

That trial is now within sight. Yankner is collaborating with researchers at Massachusetts General Hospital and Brigham and Women's Hospital on a clinical study of lithium orotate, which the Gazette reports is expected to begin this spring.

"Hopefully, in the not-too-distant future, we will have some objective data about the efficacy and safety of lithium orotate," Yankner said. "Many people are waiting for this."

A marathon, not a sprint

Yankner, a long-distance runner for much of his adult life, likes to point out that good science is a marathon. His own work bears that out: it was his research in the early 1990s that first showed amyloid was toxic to neurons, the foundation on which today's approved drugs lecanemab and donanemab are built.

This latest chapter has been ten years in the making. The next one, the one the families filling Yankner's inbox are waiting for, is only just beginning.

But for the first time in a long time, there is something concrete to hope for.