Blood protein may signal dementia risk up to 20 years in advance

(CN) — A protein circulating in the blood may serve as an early warning sign for dementia — even while possibly even playing a role in causing it.

Researchers published a study Friday in the journal Science Advances that found higher levels of the protein GDF15 measured in middle age or later life were strongly associated with increased risk of developing dementia over the following 15 to 25 years.

The link was particularly pronounced for vascular dementia, which stems from problems with blood flow to the brain, compared to Alzheimer’s disease.

“We have found that higher levels circulating in plasma are linked to really early dementia diagnosis as much as 20 years before the onset of symptoms,” study author Cassie Blew said in a phone interview. “Elevated GDF 15 levels in blood are associated with greater risk of getting dementia in the future.”

Blew and other researchers from the National Institutes of Health collaborated on the study with the National Institute on Aging, Johns Hopkins University, University College London, the Icelandic Heart Association and other institutions across the U.S., Europe and Japan.

The study drew on data from more than 20,000 participants across six major cohorts in the U.S., U.K., Iceland and elsewhere. In one analysis of middle-aged adults, those with higher GDF15 levels faced roughly a 55% greater risk of dementia over 20 years. The association held up across different sexes, races and health backgrounds, though it was sometimes weaker in people with obesity.

GDF15 is a cytokine, or a type of signaling molecule, produced mainly outside the brain, including in the kidneys. It rises with age and is involved in inflammation, appetite regulation and stress responses. While it can be protective in some contexts, in the brain’s aging environment it appears to tip toward harm, even in people with no serious health problems.

“The most remarkable thing about the paper and what we found with GDF15, is that in people that are otherwise healthy, if you have higher GDF15 in that healthy state then you have a much higher risk of dementia,” Blew said.

Using genetic tools called Mendelian randomization, the team also found evidence suggesting GDF15 doesn’t just mark risk, it may actively contribute to it.

Higher genetically predicted GDF15 levels were linked to greater odds of Alzheimer’s-related dementias, brain shrinkage and markers of brain injury.

“Our analysis showed that GDF15 can enhance inflammation in the brain, and inflammation can be good at some points, because you’re fighting stress in the brain,” Blew explained. “But at the same time that never turns off, so you’re killing immune cells that could otherwise be helping to remove amyloid plaque, which is a common feature in Alzheimer’s disease.”

In other words, the protein is trying to help, but it can help too much and make things worse.

Brain scans showed people with elevated GDF15 had more signs of small vessel disease, reduced brain volume and higher levels of another protein tied to neuron damage, even before cognitive symptoms appeared.

Notably, it wasn’t strongly tied to amyloid plaques, the classic Alzheimer’s hallmark. Instead, it pointed more toward vascular and inflammatory pathways.

In lab experiments, researchers exposed human immune cells to GDF15. It altered proteins involved in antiviral responses, energy metabolism and clearing toxins from blood. These same pathways, when measured in study participants, helped explain part of GDF15’s link to future dementia.

Dementia affects millions worldwide, and pathological changes often begin decades before symptoms. Theoretically, a simple blood test for GDF15 could one day help identify at-risk people in midlife for earlier monitoring or prevention efforts.

“That was our big push for trying to find a blood-based biomarker, because there’s nothing easily accessible in a clinic to diagnose the disease,” Blew said.

The study adds to growing evidence that systemic inflammation and vascular health are critical drivers of cognitive decline. Lifestyle steps that protect heart and blood vessel health — exercise, blood pressure control, healthy diet — may also help keep GDF15-related risks in check.

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