Plasma NfL and cognitive functioning in older adults: The moderating role of HDL cholesterol

BACKGROUND AND OBJECTIVES: Plasma neurofilament light chain (NfL) is a marker of neuroaxonal injury associated with cognitive decline. High-density lipoprotein (HDL) cholesterol has neuroprotective properties, but its interaction with neurodegeneration remains unclear. This study examined whether HDL moderates the association between NfL and cognitive performance. METHODS: Baseline data from 417 participants in the Aging Adult Brain Connectome study were analyzed. Plasma NfL and HDL were measured via Simoa and enzymatic assays; cognition was assessed using Montreal Cognitive Assessment (MoCA) and Preclinical Alzheimer Cognitive Composite (PACC). Generalized linear models were used to evaluate NfL and HDL interactions, adjusting for demographics. Sensitivity analyses included apolipoprotein E ε4, body mass index, total cholesterol, LDL, and triglycerides. RESULTS: Significant interaction effects were observed: MoCA (β = −1.86×10⁻⁴, P = 0.006) and PACC (β = −4.0×10⁻⁵, P = 0.004), indicating HDL moderates the negative association between NfL and cognition. DISCUSSION: These findings suggest that HDL modifies the cognitive impact of neurodegeneration, highlighting the importance of metabolic–neurological interactions. Highlights: High-density lipoprotein (HDL) cholesterol moderates the negative association between plasma neurofilament light chain (NfL) and cognition. Higher HDL levels intensify the negative effect of NfL on cognitive performance. Findings challenge the assumption of HDL's uniformly protective role. Results support the integrated use of metabolic and neurodegenerative biomarkers.