Abstract
Objective: Active neutrophils are important contributors to Alzheimer’s disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia.Methods: We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk.Results: The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline.Conclusion: Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted.
Highlights
The variability of amyloid-beta (Aβ) and tau pathology associated with clinical symptoms reflects that additional factors influence the progression of cognitive decline in Alzheimer’s disease (AD)
Recent studies show that neutrophils may be involved in capillary stall formation and contribute to cerebral blood flow (CBF) reductions that when sustained over time may lead to oxidative stress, endothelial damage and influence the pathological accumulation of Aβ and Recently, neutrophils have been identified as potential innate immunity players contributing to AD pathology, and a hyperactive neutrophil state has been found in patients with AD and associated with AD progression
Our study in 1,648 participants of a well-characterized community-based cohort shows an independent association of the neutrophil to lymphocyte ratio (NLR) with future dementia, reinforcing the role of neutrophil-mediated inflammation in AD pathology and progression
Summary
The variability of amyloid-beta (Aβ) and tau pathology associated with clinical symptoms reflects that additional factors influence the progression of cognitive decline in Alzheimer’s disease (AD). Clinical studies have indicated that the inflammatory status influences the rate of disease progression in patients with AD (Holmes et al, 2009; Cunningham and Hennessy, 2015). Neutrophils have been identified as potential key elements of innate immunity contribution to the disease, and a hyperactive neutrophil state has been found in patients with AD and has been associated with clinical progression (Dong et al, 2018). Results in animal models of AD have suggested that neutrophils may be implicated in the breakdown of the blood-brain barrier (BBB) and recruited in the brain parenchyma through the integrin LFA-1 predominantly in perivascular regions with Aβ deposition (Baik et al, 2014; Zenaro et al, 2015). A potential role of neutrophils in the hyperphosphorylation of tau has been suggested (Zenaro et al, 2015; Nemeth et al, 2020)
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