The relationships between cerebrospinal fluid neurofilament light chain and hippocampal atrophy with cognitive decline

Background: Identifying predictive biomarkers of cognitive decline is critical for timely intervention in early Alzheimer's disease and related dementia. Biomarkers such as cerebrospinal fluid (CSF) neurofilament light (NfL), and MRI-based hippocampal atrophy are potential indicators of neurodegeneration, but their long-term predictive value remains unclear. Objective: This study examined 20-year longitudinal associations between CSF NfL, MRI-based hippocampal atrophy, and cognitive decline in cognitively normal older adults. Methods: A cohort of 279 cognitively normal adults aged ≥55 years was followed from 2003 to 2023 at the Knight ADRC. Participants underwent annual cognitive and neurological assessments, including Clinical Dementia Rating (CDR), CSF NfL quantification, and MRI-based hippocampal volumetry. Cognitive decline was defined as: (1) first progression (CDR ≥ 0.5) and (2) sustained progression (two consecutive CDRs ≥ 0.5). Analyses included Kaplan-Meier survival, Cox proportional hazards models, and linear mixed-effects (LME) models. Results: Participants had a mean age of 66.5 years (SD = 6.08); 58.4% were female. Mean follow-up was 11.41 years (SD = 3.5). First progression occurred in 71 participants (25.4%), and sustained progression in 35 (13%). Higher CSF NfL levels were associated with faster time to first (95% CI:0.2–1; p < 0.001) and sustained progression (95% CI:0.46–1; p = 0.008). Cox models showed increased risk of first progression (HR = 1.83; 95% CI: 1.11–3.01; p = 0.018) but not sustained (p = 0.093). LME models showed CSF NfL increase and hippocampal volume decline (p < 0.001) in both outcomes. Conclusions: CSF NfL is a strong predictor of cognitive decline and may serve as a screening biomarker for early dementia risk.