Neutrophil-to-Lymphocyte Ratio in the Alzheimer's Disease Continuum

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder defined clinically by progressive cognitive decline and memory impairment and pathologically by the accumulation of amyloid-beta plaques, tau neurofibrillary tangles, neuroinflammation, and immune system dysregulation. Peripheral biomarkers are gaining attention as valuable tools for elucidating neuroinflammatory mechanisms in the AD continuum, with potential implications for diagnosis and prognosis. Among these, the neutrophil-to-lymphocyte ratio (NLR) has emerged as a promising systemic inflammatory marker. NLR, a readily available and cost-effective parameter derived from routine blood tests, reflects the balance between innate and adaptive immune responses. Elevated NLR has been associated with AD and mild cognitive impairment (MCI), showing correlations with disease severity, amyloid burden, and neuroinflammation. Increased neutrophil counts may contribute to neurodegeneration through oxidative stress and pro-inflammatory cytokine release, while decreased lymphocyte levels suggest impaired adaptive immunity. However, despite growing evidence, the clinical utility of NLR in AD remains debated due to heterogeneity in study populations and confounding factors, such as comorbidities and medication effects. This review provides a comprehensive analysis of the association between NLR and AD throughout the disease continuum. Future research should prioritize longitudinal studies and integrative approaches that combine NLR with other inflammatory and neurodegenerative markers to enhance early diagnosis and personalized therapeutic strategies.

Keywords: biomarkers; cognitive decline; mild cognitive impairment; neuroinflammation.

Figure 1

Blood–brain barrier breakdown in Alzheimer’s disease pathology. This schematic representation illustrates the involvement of NLR in AD, emphasizing its contribution to neuroinflammation and BBB dysfunction. The pathological brain in AD is characterized by amyloid plaque accumulation and neurofibrillary tangles, leading to neuronal damage and activation of reactive astrocytes. Increased NLR reflects a systemic inflammatory response, with elevated neutrophils contributing to oxidative stress, cytokine release, and endothelial dysfunction, ultimately promoting BBB breakdown. The compromised BBB allows peripheral immune cells, including neutrophils, monocytes, and platelets, to infiltrate the brain parenchyma, exacerbating neurodegeneration. These processes collectively drive chronic neuroinflammation, neuronal death, and cognitive decline in AD. Abbreviations: BBB: blood–brain barrier; IL: interleukin; TNF: tumor necrosis factor. Created with Biorender.com (De Marchi F.).

Figure 2

Key confounding factors influencing the value of NLR in cognitive decline. The figure highlights the main confounding factors that can affect NLR levels and impact cognitive decline studies. These include demographic, genetic, medical, lifestyle, and protective brain health variables, each with distinct mechanisms potentially influencing both NLR and neurodegeneration. NLR: neutrophil-to-lymphocyte ratio. Created with Biorender.com (De Marchi F.).