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Circulating white blood cells called neutrophils are some of the immune system’s first responders. Their numbers shoot up during infection and inflammation, shifting the ratio of neutrophils to other types of immune cells in the blood.

This ratio, called the neutrophil to lymphocyte ratio (NLR), is easily obtained from a complete blood cell count, which is used by clinicians to diagnose infection and other immune conditions.

Now, a new study led by researchers at 91����Ƶ Langone Health shows that a high NLR could identify patients at risk of developing Alzheimer’s disease and related dementias before they exhibit any signs of cognitive impairment. The researchers analyzed NLR data from nearly 400,000 patients from two health care systems.

“Our study is the first large-scale investigation showing that neutrophil metrics are associated with increased risk of dementia in humans,” said study first author Tianshe (Mark) He, PhD, a data scientist in the Department of Psychiatry at 91����Ƶ Grossman School of Medicine. “Neutrophil elevation is happening before any evidence of cognitive decline, which makes a compelling case for studying whether neutrophils are actively contributing to disease progression.”

Dr. He and study co-senior author , an assistant professor in the Departments of and at 91����Ƶ Grossman School of Medicine, are both affiliated with the VA Boston Healthcare System’s Cooperative Studies Program.

Published in the journal online April 3, the new study includes data from nearly 285,000 patients at four 91����Ƶ Langone hospitals and nearly 85,000 patients from the Veteran’s Health Administration.

For each patient, the researchers selected the earliest available NLR measurement matching their study criteria: It had to fall within the timeframe of their study, and the patient had to have been at least 55 years old. The measurement also had to have occurred before the patient received an Alzheimer’s or dementia diagnosis. Then, the researchers checked whether the person later received a dementia diagnosis within the study window.

They found that in each study population, an elevated NLR result was significantly associated with both long-term and short-term risk of Alzheimer’s and dementia. High NLRs were based on the median, or midway point, meaning half of the group had NLRs above it and half had NLRs below it.

The researchers noted that the risk tied to the NLR values was higher for Hispanic patients, although it is not yet clear if this is due to genetic factors or social ones, such as disparities in healthcare access. The risk was also higher for women in both health systems evaluated.

The results are significant for two reasons, said Dr. Ramos-Cejudo, who also serves as director of the Vascular and Immune Dysfunction in Aging and Alzheimer’s Disease (VIDA) lab at 91����Ƶ Langone. By itself, an elevated NLR is likely not sufficient to predict future dementia risk. However, when combined with other risk factors, it could help identify people who should undergo more comprehensive testing and maybe begin treatment before signs of cognitive decline appear.

The other reason the results are compelling is that they add to a growing body of evidence that neutrophils may be actively involved in dementia progression, said Dr. Ramos-Cejudo.

Although neutrophils are important for healing wounds, they can cause the sort of tissue damage at the vascular level that has been seen in Alzheimer’s and dementia. Neutrophil inflammation has been found in brain pathology of Alzheimer’s patients, and studies in mice show that neutrophils accelerate Alzheimer’s disease progression. It is also possible that aging changes the body’s natural recycling of neutrophils, leading to tissue damage from disruptions in routine removal.

But a clear link between Alzheimer’s, dementia, and neutrophils has not yet been established. This is largely because neutrophils are constantly being recycled and only live for a few days, so they must be studied from fresh blood samples, unlike cell types that can be stored and frozen.

Dr. Ramos-Cejudo said his group at the VIDA lab is investigating whether neutrophils are contributing to cognitive decline in Alzheimer’s and dementia patients. They are doing so by combining measurements of neutrophil activity with multiple brain imaging techniques (such as PET and diffusion MRI) and cognitive testing in patients.

“These and future studies will show whether neutrophils are just a marker of Alzheimer’s disease or are actively causing dementia progression — in which case, they could make a compelling therapeutic target,” said Dr. Ramos-Cejudo. “In the meantime, we hope the neutrophil to lymphocyte ratio can contribute to gateway diagnostic tools for people at risk of developing Alzheimer’s and dementia, so they can get more in-depth testing and interventions long before they experience cognitive decline.”

Funding for the study was provided by National Institutes of Health grants R01AG092953, R01AG070821, R01AG079282, P30AG066512, K23AG068534, R01AG082278, and RF1AG083975. Additional funding was provided by the National Alzheimer's Coordinating Center, the VA Boston Healthcare System’s Cooperative Studies Program, Alzheimer’s Association grant AARG-21-848397, and BrightFocus Foundation grant A2022033S.

Other 91����Ƶ researchers involved in the study were Rebecca A. Betensky, PhD; Ricardo S. Osorio, MD; Tovia Jacobs; Alok Vedvyas, MS, MSJ; Karyn Marsh, PhD; Joshua Chodosh, MD; Ula Y. Hwang, MD, MPH; Natalia Sifnugel, MPH; Omonigho M. Bubu, MD, PhD, MPH; and Thomas Wisniewski, MD.

Other study co-investigators were Chunlei Zheng, PhD; Kaitlin Swinnerton, MIDS; Mary Brophy, MD; and Nhan V. Do, MD, at the VA Boston Healthcare System’s Cooperative Studies Program (MAVERIC). Nathaniel Fillmore, PhD, at Harvard Medical School, was the study’s co-senior author.

About 91����Ƶ Langone Health

91����Ƶ Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked 91����Ƶ Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. 91����Ƶ Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

Media Contact:

David March
212-404-3528
David.March@91����ƵLangone.org