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

BackgroundIdentifying 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.ObjectiveThis study examined 20-year longitudinal associations between CSF NfL, MRI-based hippocampal atrophy, and cognitive decline in cognitively normal older adults.MethodsA 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.ResultsParticipants 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.ConclusionsCSF NfL is a strong predictor of cognitive decline and may serve as a screening biomarker for early dementia risk.