Neutrophils, a type of white blood cell that circulate in the bloodstream, serve as part of the body’s first responders to infection and inflammation. When the immune system is activated, its number increases rapidly and the balance between neutrophils and other immune cells changes.
Doctors can measure this balance using a standard test called the neutrophil-to-lymphocyte ratio (NLR). This number is routinely calculated from a complete blood count, a common test used to detect infections and assess immune health.
A new study from NYU Langone Health suggests this simple measurement may do more than reflect current illness. It could also help identify people at high risk of developing Alzheimer’s disease and related dementias, even before symptoms appear. This study examined NLR data from approximately 400,000 patients across two large health systems.
Large-scale study shows link between immune cells and dementia risk
“Our study is the first large-scale study to show that neutrophil indicators are associated with increased risk of dementia in humans,” said Tianxie (Mark) He, Ph.D., lead author of the study and a data scientist in the Department of Psychiatry at New York University’s Grossman School of Medicine. “The rise in neutrophils occurs before signs of cognitive decline and provides a compelling basis to study whether neutrophils actively contribute to disease progression.”
Dr. He and co-senior author Dr. Jaime Ramos Cejudo, assistant professor in the Department of Psychiatry and Neurology at New York University Grossman School of Medicine, are both affiliated with the VA Boston Healthcare System Cooperative Research Program.
The study, published online April 3 in the journal Alzheimer’s & Dementia, includes data from about 285,000 patients treated at four New York University Langone hospitals and about 85,000 individuals at the Veterans Health Administration.
To ensure accuracy, the team used each patient’s earliest eligible NLR measurement. These measurements had to be within the study period, taken when the patient was at least 55 years old, and before receiving a diagnosis of Alzheimer’s disease or dementia. The researchers then tracked whether these people developed dementia during the study period.
Increased NLR is associated with short-term and long-term risks
Across both groups, higher NLR levels were consistently associated with an increased likelihood of developing Alzheimer’s disease or other forms of dementia. This relationship applies to both short-term and long-term risks. The researchers defined “high” NLR based on the median value. This means that half of the participants had higher readings and the other half had lower readings.
The analysis also revealed differences between subgroups. In Hispanic patients, elevated NLR was shown to be strongly associated with dementia risk, but it remains unclear whether this reflects genetic influences or social factors such as differences in access to care. Women in both health care systems were at higher risk associated with elevated NLR.
Why this blood marker is important
According to Dr. Ramos Cejudo, this finding is important for two main reasons. High NLR alone is unlikely to serve as a definitive predictor of dementia. However, when combined with other known risk factors, it may help identify individuals who may benefit from close monitoring, additional testing, or early intervention before cognitive symptoms appear.
The results also support growing evidence that neutrophils may play a more active role in the disease process itself.
Immune cells may drive Alzheimer’s disease progression
Neutrophils are essential for fighting infections and helping tissue repair, but under certain conditions they can also contribute to damage. In Alzheimer’s disease and other dementias, this damage can occur in blood vessels and brain tissue. Signs of neutrophil-mediated inflammation have been observed in the brains of Alzheimer’s patients, and animal studies suggest that these cells may accelerate the progression of the disease.
The situation may be further complicated by an aging population. Because the body’s ability to remove old neutrophils changes over time, disruption of this process can lead to increased tissue damage.
Still, researchers caution that a direct cause-and-effect relationship has yet to be confirmed. One challenge is that neutrophils have a very short lifespan and must be studied using fresh blood samples, unlike other cell types, which can be stored for later analysis.
Ongoing research into diagnosis and treatment
Dr. Ramos Cejudo and colleagues in the Vascular and Immune Dysfunction in Aging and Alzheimer’s Disease (VIDA) Laboratory are continuing to study whether neutrophils actively contribute to cognitive decline. Their study combined measurements of neutrophil activity with advanced brain imaging (such as PET and diffusion MRI) and cognitive assessment of patients.
“Previous and future studies will determine whether neutrophils are simply markers of Alzheimer’s disease or whether they actively drive the progression of dementia, in which case they may represent an attractive therapeutic target,” said Dr. Ramos-Cejudo. “In the meantime, we hope that the neutrophil-to-lymphocyte ratio can contribute to a gateway diagnostic tool for people at risk of developing Alzheimer’s disease and dementia, allowing them to receive more detailed testing and intervention long before they experience cognitive decline.”
Funding and research team
This research was supported by National Institutes of Health grants R01AG092953, R01AG070821, R01AG079282, P30AG066512, K23AG068534, R01AG082278, and RF1AG083975. Additional funding was provided by the National Alzheimer’s Disease Coordinating Center, the VA Boston Healthcare System Collaborative Research Program, Alzheimer’s Association grant AARG-21-848397, and BrightFocus Foundation grant A2022033S.
Other New York University researchers involved in the study were Rebecca A. Betensky, Ph.D.; Dr. Richard S. Osorio; Tobia Jacobs. Alok Vedvyas, MS, MSJ. Dr. Karin Marsh. Joshua Chodosh, MD. Ulla Y. Huang, MD, MPH. Natalia Schifnugel, MPH. Omonigo M. Bubu, MD, PhD, MPH. and Dr. Thomas Wisniewski.
Additional collaborators include Dr. Chunlei Zheng; Caitlin Swinnerton, MIDS. Mary Brophy, MD. and Nhan V. Do, MD, of the VA Boston Healthcare System Collaborative Research Program (MAVERIC). Dr. Nathaniel Fillmore of Harvard Medical School also served as co-senior author.
