Neutrophil-to-Lymphocyte Ratio as a Scalable Signal in Dementia Risk Assessment

Growing evidence continues to support a role for systemic inflammation in the development and progression of Alzheimer disease (AD) and related dementias, with increasing interest in identifying scalable biomarkers that can be integrated into real-world clinical practice. While advances in blood-based biomarkers targeting amyloid and tau have reshaped early detection strategies, there remains a need for accessible, cost-effective signals that may help identify at-risk individuals prior to the onset of cognitive symptoms.

Recently published research in Alzheimer’s & Dementia analyzed data from more than 370,000 patients across 2 large health systems, examining the association between neutrophil-to-lymphocyte ratio (NLR) and future risk of AD and AD-related dementias. The study demonstrated that elevated NLR was consistently associated with increased dementia risk across cohorts, with hazard ratios ranging from 1.07 to 1.21 after adjusting for demographic and clinical variables. Notably, analyses suggested a continuous dose-response relationship, with progressively higher risk observed across increasing NLR levels rather than at a single threshold.

In this Q&A, Jaime Ramos, PhD, Assistant Professor of Psychiatry and Neurology at NYU Grossman School of Medicine and co-senior author of the study, discusses how NLR may fit into existing risk stratification frameworks, its potential mechanistic links to neurodegeneration, and the clinical considerations and limitations of using this widely available marker in practice. He also outlines the additional validation needed before NLR could be incorporated into broader clinical or research applications.

NeurologyLive: Can you summarize the key findings of this large-scale analysis, particularly the strength of association between elevated neutrophil-to-lymphocyte ratio and future dementia risk?

Jaime Ramos, PhD: Our study analyzed over 370,000 patients across two large health systems (NYU Langone and the VA) and found that higher neutrophil-to-lymphocyte ratio was consistently associated with increased risk of future Alzheimer’s disease and AD-related dementias. Using IPW Cox models, elevated NLR was associated with a 7% higher risk in the NYU cohort (HR 1.07) and a 21% higher risk in the VA cohort (HR 1.21) after adjusting for demographics and comorbidities. Importantly, spline analyses showed a continuous dose-response relationship, meaning risk increased progressively with higher NLR rather than only at extreme values.

From a clinical perspective, how might NLR be integrated into current risk stratification approaches, particularly in asymptomatic patients?

We are not really considering NLR as a diagnostic tool for Alzheimer disease by itself. However, we believe it is an easy-to-access and scalable risk signal that could complement existing risk stratification frameworks. Prior work from our group and others shows that NLR associates with AD risk biomarkers and MRI markers of brain aging in cognitively unimpaired individuals. In asymptomatic patients, NLR could help identify those with a systemic inflammatory profile who may benefit from closer monitoring or inclusion in prevention strategies.

Inflammation is gaining momentum in Alzheimer disease research, and recent studies suggest that systemic inflammation facilitates an environment conducive to the progression of AD pathology. NLR could provide value when incorporated into multivariable risk models alongside age, vascular risk factors, and emerging AD-specific blood biomarkers.

What are the potential mechanistic links between neutrophil activity and neurodegeneration, and how do you view NLR in this context?

Our view in the VIDA Lab at NYU is that inflammation is not simply background noise in Alzheimer disease. An increase in neutrophil markers may reflect increased inflammation at the neurovascular unit level. Studies in animal models support a direct role of neutrophils in blood-brain barrier dysfunction, chronic inflammation, and alterations in neutrophil signaling and clearance.

We think that increases in NLR could be interpreted both as a biomarker of systemic immune imbalance and as a potential window into biological pathways that may actively contribute to disease progression.

Given that NLR is derived from a routine CBC, what are the advantages and limitations of using this metric compared with more established biomarkers?

The major advantage is practicality. NLR is widely available and derived from a routine complete blood count, which is performed in millions of patients every day. While neutrophil biology is complex and NLR is a relatively simple proxy reflecting their relative abundance, it is attractive for population-scale research and potential clinical enrichment strategies.

The main limitation is that NLR is nonspecific. It can be influenced by infection, medications, cancer, autoimmune disease, stress, smoking, obesity, and many other conditions. It also does not directly measure Alzheimer pathology, so it should be interpreted as an inflammatory or immune risk signal rather than a diagnostic biomarker.

What additional validation is needed before NLR could be used more broadly in clinical or research settings?

Before potential clinical adoption, we would need prospective longitudinal studies with repeated NLR measurements, demonstration that NLR adds predictive value beyond established risk factors and AD-specific biomarkers, and integration with imaging and molecular biomarkers such as amyloid and tau.

We also need a better understanding of thresholds and trajectories over time, not just single measurements. Additionally, studies should evaluate whether treatments that reduce Alzheimer disease risk are partially mediated by reductions in NLR, reinforcing the role of inflammation as a contributor.

In general, NLR is a scalable marker reflecting systemic inflammation, but it requires further validation before being used for risk stratification. Perhaps the most important conclusion is that our study highlights the importance of understanding the role of peripheral inflammation and neutrophil biology in Alzheimer disease going forward.

Transcript edited for clarity.

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