To evaluate the association between peripheral immune markers and future risk of mild cognitive impairment (MCI) and dementia, their ability to differentiate between dementia causes, and their correlation with disease severity and pathological markers.
Systemic inflammation and innate immune activation have been linked to dementia, but prior studies were limited by small sample sizes. Key uncertainties remain, including the prospective risk of dementia, differential associations with dementia causes, and correlations with disease severity and pathological markers.
We conducted a systematic review and meta-analysis of studies assessing peripheral immune markers and prospective dementia outcomes. Exposures included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammatory index (SII). Outcomes were risk of MCI and dementia (including Alzheimer’s disease, vascular dementia, and Parkinson’s disease dementia), dementia severity assessed by the Mini-Mental State Examination, and cerebrospinal fluid pathological markers including amyloid-β42 (Aβ42), amyloid-β40 (Aβ40), and tau. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled as effect estimates.
Our analysis included 947,020 participants from 23 studies. NLR and SII, but not PLR, were associated with increased risk of dementia (NLR: HR = 1.24, 95% CI: 1.15–1.34; SII: HR = 1.08, 95% CI: 1.03–1.13) and MCI (NLR: HR = 2.78, 95% CI: 1.57–4.90; SII: HR = 1.28, 95% CI: 1.04–1.56). No differential associations were observed across dementia causes. NLR and SII correlated with worse dementia (NLR: r = –0.22, p=0.033; SII: r = –0.17, p=0.041) and MCI severity (NLR: r = –0.30, p=0.010; SII: r = –0.23, p=0.025). NLR, but not SII, was associated with Aβ42, Aβ40, and tau.
NLR and SII are inexpensive, widely accessible biomarkers associated with dementia risk, severity, and pathological markers. They may provide valuable insights where advanced biomarker testing is unavailable due to technological or financial barriers.