Six large studies. Tens of thousands of people. Follow-up of 15 to 25 years. Put together, the data point to a single blood protein that may flag dementia risk long before a family notices anything wrong.
The protein is GDF15, found in blood plasma. An international team reported in Science Advances that people with higher GDF15 levels at age 55 or younger were more likely to develop dementia in the decades that followed.
The link between GDF15 and dementia is not brand new. Higher levels in the blood had already been associated with dementia later in life. What the researchers added is that the association holds below age 55, which puts the signal in middle age.
What the researchers did
The team first pooled six independent cohort studies from the US, the UK, Iceland and Japan. Each had blood sample readings plus health records for follow-up periods of 15 to 25 years. The relationship was strongest for vascular dementia, which is caused by disruptions to the brain’s blood supply. The researchers tentatively tied that to GDF15’s role in inflammation.
Next came Mendelian randomization, a technique that uses genetic patterns as stand-ins for something else, here elevated GDF15 in the blood. Combining genetic datasets covering hundreds of thousands of people, the team found that those with variants linked to higher GDF15 also had a higher risk of dementia. Because those genes do not depend on lifestyle, environment or disease, the result hints that the protein may be a driver of dementia and not only an early sign.
In smaller datasets the researchers looked at brain scans and cerebrospinal fluid. More GDF15 in the blood went with more in the fluid around the brain, and with brain shrinkage, but not with the toxic amyloid beta clumps tied to Alzheimer’s disease. “We observed a strong correlation between plasma and CSF GDF15 levels, which is consistent with the possibility that circulating GDF15 crosses into the central nervous system,” the researchers wrote.
A possible mechanism
Lab tests on immune cells found GDF15 interfering with normal pathways for immune responses and energy management. One of the protein’s main jobs is keeping the immune system in check, and the researchers suggest it may quiet that system too much in dementia, leaving the brain vulnerable. “Our results suggest plasma GDF15 may function as an early risk factor for dementia risk by modulating metabolic pathways and the neuroimmune axis,” they wrote.
Much more work is needed to confirm that. Down the line, the team says, GDF15 could help doctors spot higher dementia risk early and help scientists understand how the disease develops.
Families watching a parent’s memory slip may take some comfort in the direction of the research, even though this is a risk marker and not a treatment. “These findings support circulating GDF15’s role as an early biomarker, particularly for vascular dementia and neuroinflammation,” the authors concluded.
