Elevated levels of a blood protein called growth differentiation factor 15 during midlife were associated with about twice the incidence of dementia over the next 20 years. This protein is released from cells during aging, inflammation, and other biological stresses. This research scientific progressprovides evidence linking this protein to future cognitive decline.
Previous research has identified this protein as a potential early warning sign of dementia. But scientists weren’t sure whether it simply reflected poor health or actually contributed to damaging brain processes. To find out, researchers investigated whether blood levels of this protein predicted different forms of dementia. They also looked at whether it was associated with brain changes, genetic risk, and immune activation.
A team led by Cassandra O. Belew of the National Institutes of Health combined evidence from six large studies that followed participants over time. The main midlife analysis included 11,595 American adults with a mean age of 57 years. These participants were followed for approximately 20 years. The scientists also analyzed data from older Americans, British participants, and Icelandic adults with an average age of 60 to 76 years.
The researchers measured proteins in blood samples to examine subsequent diagnoses of all forms of dementia, including Alzheimer’s disease and vascular dementia. The statistical model took into account factors such as age, gender, kidney function, smoking, obesity, diabetes, and genetic susceptibility. The results showed that in a sample of middle-aged Americans, each doubling of protein levels increased the risk of developing dementia by 55 percent.
Among participants with protein levels in the top half of the group, 7.5 percent developed dementia within 20 years, compared with 3.9 percent of participants in the bottom half. A similar pattern emerged in a group of older Americans over a seven-year period. In that elderly group, 18.7 percent of those with high levels developed dementia, compared to 9.5 percent of those with low levels.
This relationship was stronger for vascular dementia than for Alzheimer’s disease. Vascular dementia is caused by reduced blood flow and damage to blood vessels in the brain, while Alzheimer’s disease is associated with the accumulation of abnormal proteins. In the UK sample, each doubling of protein increased the risk of vascular dementia by 101 percent, but the risk of Alzheimer’s disease increased by only 20 percent. A group from Iceland made similar estimates, showing a 106 percent higher risk for vascular dementia, but a 24 percent higher risk for Alzheimer’s disease.
Brain scans provided matching evidence. They found that higher levels of the protein led to smaller brain volume, thinner brain tissue, and more damage to white matter, the network of nerve fibers that connect different brain regions. Increased protein also predicted increased odds of small strokes and microscopic cerebral hemorrhages. This finding suggests that this protein is more implicated in blood vessel damage, general brain tissue loss, and inflammation, rather than a specific protein pathway in Alzheimer’s disease.
Genetic analysis provides evidence that this protein may play a direct role in causing brain changes. To investigate this, the research team conducted experiments using macrophages, immune cells that engulf and destroy cellular debris. The researchers exposed macrophages from six adults to the growth differentiation factor 15 protein. This exposure altered immune and energy-related pathways within the cell, including reducing antiviral signaling and inhibiting the removal of free heme, an iron-rich molecule that can be toxic when released from red blood cells.
The authors concluded that their findings support a role for this circulating protein as an early warning sign of vascular dementia and brain inflammation in particular. The researchers noted that the results could also help identify biological mechanisms by which this protein may cause dementia risk.
Several limitations limit the study’s conclusions. Blood proteins added little predictive information about dementia risk across a person’s age. The research program also cannot conclusively prove that the protein causes the disease. Finally, the association between this protein and dementia was not statistically significant in a small Japanese group of 340 people, suggesting that further research is needed across different populations.
The paper, “Plasma GDF15 influences long-term dementia risk and alters neuroimmune signaling,” was authored by Cassandra O. Blew, Michael R. Duggan, Dimitrios Tsitsipatis, Gabriela T. Gomez, Zulema Rodriguez-Hernandez, Luke C. Pilling, Jingsha Chen, Eva Jacobsen, Heather E. Dark, Yifei Lu, and Shannon M. Drouin, Cassandra M. Joines, Minghao Yao, Murat Bilgel, Abai Mogekal, Qu Tian, Julián Candia, Mary Kaile, Aditi Gupta, Christina Mazan-Mamzarz; Miriam Gorospe, Alexei Lyashkov, Evgeniya Lukyanenko, Mika Kivimäki, Philip Frank, Lori L. Jennings, Valborg Guðmundsdottir, Virmundur Gudnason, Lenore J. Rauner, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Keita Hiraga, Yukiko Nishida, Rei Otsuka, James R. Pike, Mary R. Rooney, Pascal Schlosser, Yuhan Kui, Gray Els, Chris Tos Davatzikos, Rebecca F. Gottsman, Iwao Waga, Priyaparta, Christy Ballantine, Michael Griswold, Zhonghua Liu, Luigi Ferrucci, Alison B. Herman, Keenan A. Walker.
