Neutrophil-to-lymphocyte ratio, not C-reactive protein, is associated with midlife cognition

INTRODUCTION: Systemic inflammation is implicated in Alzheimer's disease, but its role during preclinical stages and interaction with apolipoprotein E ε4 (APOE ε4) remain unclear. METHODS: We analysed longitudinal serum C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR) in 441 cognitively healthy midlife adults from the PREVENT Dementia cohort, sampled three years apart. Cognition was assessed using the Addenbrooke's Cognitive Examination III, adjusted for site, age, sex, education, and APOE ε4. RESULTS: A longitudinal increase in NLR, but not CRP, was associated with midlife cognitive decline (β = -0.763, p = 0.031), independent of APOE ε4. In exploratory analyses, APOE ε4 carriers had lower baseline CRP than non-carriers, a difference that attenuated over follow-up; NLR showed no such association. DISCUSSION: Rising NLR may be a more sensitive marker of early midlife cognitive change than CRP, suggesting it captures immune dysfunction beyond systemic inflammation.