At long last, we now have a disease-modifying drug for Alzheimer’s. By the end of this year, we’ll likely have another. But although these treatments can modestly slow the inexorable march of the disease, there’s a clear need to treat patients earlier and to find other drugs that have a stronger effect. But how early is early enough? And what other drugs? New research out of a decades-long study offers some new ideas about both.
Eisai and Biogen’s treatment Leqembi, and a second drug from Eli Lilly called donanemab, both reduce levels of the amyloid plaques long considered a hallmark of the mind-robbing disease. Data so far suggests that these drugs can ease the decline in people with mild forms of the disease by around 30%. To get beyond that, the field needs to put more energy into identifying and testing for the less obvious actors contributing to the disease potentially decades before symptoms arise.
“These amyloid-clearing drugs appear to work — that’s fantastic,” says Keenan Walker, a neuroscientist at the National Institute on Aging, and lead author of the new study. “They’re slowing disease, but they’re not halting it. We’re going to need to target other pathways to achieve better outcomes.”
So far, much of the focus of drug development beyond amyloid has been on the other obvious player in Alzheimer’s disease, tau, another protein that tangles together in the brains of people with the disease. And targeting amyloid and tau made sense. After all, they light up on specialized brain scans and, increasingly, can be detected in the blood tests, diagnostic tools that transformed the way Alzheimer’s drugs were tested.
But the legions of amyloid-targeted drugs that came before Leqembi and donanemab made clear that plaques aren’t the only culprit — or even maybe the main culprit — in the disease. Other processes unquestionably contribute to the memory loss and overall declining function of people with the disease — likely ones that happen well before amyloid or tau might show up on a brain scan. Now, as technology makes it easier to winnow those players out, scientists should step up the search for alternate or even complementary approaches to diagnosing and treating Alzheimer’s even earlier.
The new study provides some good clues about other players involved at the very earliest stages of the disease. The team found a collection of proteins that appear perturbed in midlife in the people who go on to develop Alzheimer’s disease 15 or even 25 years down the road. Many of those proteins were not directly involved with amyloid and tau, but instead were involved in immune processes, communication between nerve cells, and protein regulation.
The NIA team was able to find this potential sign of early risk by capitalizing on a rich data source: nearly 15,800 people recruited when they were between the ages of 45 and 64 for a long-term study of atherosclerosis, or buildup of plaque in the arteries. Those volunteers began rolling up their sleeves in the mid-1980s — before Walker was even born — and still are being followed today.
As part of that atherosclerosis study, participants agreed to regularly answer questions about their health and come in every few years for an exam. By 2010, as people in the group started hitting their 70s and 80s, researchers added in a new battery of tests to capture everyone with dementia. Using health records, they could even track Alzheimer’s development among patients lost to attrition — giving them an overall group of nearly 11,000 people to study.
In the decades since they started following these folks, technology has raced ahead. The NIA team could go back to those early samples and, in a cost-effective, reliable way, take inventory of thousands of proteins contained within each person’s plasma to ask if any were associated with a risk of Alzheimer’s later in life.
They came up with a list of a few dozen proteins that were more prominently expressed in people who went on to develop the disease. But one, called GDF15, rose above the crowd, Walker says. That protein seems to be involved with regulating certain kinds of inflammation and, although it had been linked to Alzheimer’s and other neurodegenerative diseases, it has until now never been shown to be a predictor of dementia.
Further digging showed that while it’s a predictor, it’s not a driver of the disease, Walker says. The researchers hypothesize that it is likely an anti-inflammatory molecule that is kicking into action in response to some danger — a process that is happening as early as someone’s 40s. That adds to a growing body of evidence from genetic studies pointing to the immune system’s role in the disease long before plaques can be seen in a brain scan.
These findings aren’t an early test for Alzheimer’s risk; they don’t even clearly identify a target for new drugs. But by flagging these proteins, the study could help scientists better understand the very early processes that set some people on the path to dementia. That, in turn, could lead to better ideas for drugs and tests.
For too long, the field has focused on the obvious targets of amyloid and tau. Happily, that work is finally bearing fruit, but getting closer to cures will require a deeper understanding of the early stages of this disease.
Lisa Jarvis is a Bloomberg Opinion columnist covering biotech, health care and the pharmaceutical industry. Previously, she was executive editor of Chemical & Engineering News.
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