Neutrophil-to-lymphocyte ratio predicts early cognitive decline associated with tau pathology in Alzheimer's disease: a longitudinal study of the ADNI cohort.

Abstract

Background Neuroinflammation is a key driver of Alzheimer's disease (AD). Although the neutrophil-to-lymphocyte ratio (NLR) is an easily accessible peripheral inflammatory marker, yet its longitudinal association with domain-specific cognitive decline and the underlying neuropathological mechanisms during the preclinical and early stages of AD remain unclear. Methods A total of 1,190 non-people living with dementia older adults from the AD Neuroimaging Initiative cohort were included, comprising 405 cognitively normal participants and 785 participants with mild cognitive impairment (MCI). Participants were stratified according to baseline NLR (≥ 3versus < 3). Linear mixed-effects models were used to examined the association between baseline NLR and longitudinal decline across multiple cognitive domains. Cox proportional hazards model assessed progression risk to MCI or AD. Mediation analyses evaluated whether cerebrospinal fluid (CSF) biomarkers, including amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau), statistically accounted for the association between NLR and cognitive decline. Results During follow-up, a high baseline NLR (≥ 3) was independently associated with accelerated decline in global cognition, memory, executive function, language, and visuospatial abilities (all p < 0.05), as well as a 20% higher risk of clinical progression per 1-unit increase in NLR (hazard ratio = 1.20, 95% confidence interval: 1.12-1.29, p = 0.001). Mediation analyses indicated that CSF t-tau and p-tau, but not Aβ42, partially explained the association between NLR and cognitive decline. The observed associations remained robust across sensitivity and subgroup analyses. Conclusion Elevated NLR was significantly and independently associated with accelerated decline across multiple cognitive domains and an increased risk of clinical progression in older adults at risk for AD. The observed associations with tau pathology are consistent with a potential role for peripheral immune dysregulation in early disease trajectories; however, formal predictive modeling and external validation are required before clinical application.