A common blood test for inflammation may serve as a warning sign of increased Alzheimer’s disease risk, in apparent contrast to other recent discoveries about how the immune system influences brain health and function, according to a large new study.
Neutrophils, the circulating white blood cells, are among the immune system’s first responders. While circulating in the blood, neutrophils exist at a relatively stable ratio to other immune cells within healthy individuals; their numbers increase dramatically during infection and inflammation.
This balance is expressed as the neutrophil-to-lymphocyte ratio (NLR), a simple CBC measurement routinely used in clinical settings to assess infection and immune status.
Now, researchers who have studied large health records propose that this common marker may also be a possible tool for identifying those most at risk of developing Alzheimer’s disease and related dementia before clinical manifestations appear.
STUDY DESIGN: Cross-sectional analysis of electronic health records recorded between 2011 and 2023 across two large health systems: New York University (NYU) hospitals (n=284,530) and the Veterans Health Administration (VA) (n=85,836). Baseline NLR measurements were obtained, and patients were followed to ascertain incident Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD), with diagnoses confirmed at least 6 months after the date of blood sampling using ICD codes.
A higher NLR was consistently associated with an increased risk of dementia among both cohorts. The relationship remained significant after accounting for demographic and clinical variables, using statistical modeling that treated mortality as a competing risk.
In the NYU cohort, high NLR was associated with increased risk of AD/ADRD (hazard ratio [HR] = 1.07, 95% confidence interval [CI] 1.02–1.15). This relationship was more prominent in the VA cohort (HR = 1.21, 95% CI 1.10–1.34). In particular, the spline analyses consistently revealed a dose–response relationship, showing that dementia risk increased gradually with higher NLR rather than at any specific threshold.
“These results indicate that higher NLR was independently and positively associated with risk of future AD/ADRD,” the researchers noted, adding that subgroup analyses showed consistently higher risk among female and Hispanic participants.
“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 NYU 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.”
The results contribute to the body of evidence behind systemic inflammation as a driver of neurodegeneration. Although neutrophils are involved in the fight against infection and in tissue repair, they have also been implicated in causing vascular damage and oxidative stress, both of which contribute to the pathology of Alzheimer’s disease. Neutrophils have previously been shown to potentiate the progression of brain disease in experimental mouse studies.
However, the researchers cautioned that the relationship has not been completely explained.
“Elevated NLR is independently associated with higher AD/ADRD risk across diverse populations, highlighting the role of systemic inflammation and neutrophil-mediated pathways in neurodegeneration,” the study authors wrote in their discussion.
They also note that small sample sizes have limited earlier investigations linking NLR to dementia. On the other hand, the present study is based on one of the largest datasets available. It uses sophisticated statistical methods, such as inverse probability-weighted Cox models and cumulative incidence function estimation, to increase the reliability of the results.
Although the correlation is so strong, the researchers caution that NLR, on its own, will rarely be sufficient as a diagnostic marker. Instead, it would help to develop a generalized risk assessment model to identify which individuals may be suitable for an earlier and more extensive neurological workup.
The biological mechanisms of this relationship are still under examination. Systemic chronic inflammation, age-related changes in immune cell turnover, or neutrophil-induced vascular damage have been hypothesized to contribute to long-term brain health.
The initial neutrophil-to-lymphocyte ratio is just a common marker of infection. Still, as work in this area becomes more advanced, it could serve well and show promise as a prognosticator of the earliest signs of cognitive decline.
Journal Reference:
Tianshe He, Rebecca A. Betensky, Ricardo S. Osorio, Kaitlin Swinnerton et al. Neutrophil inflammation metrics are associated with the risk of future dementia in large data from NYU Langone Hospitals and the Veterans Health Administration. Alzheimer’s & Dementia. DOI: 10.1002/alz.71335