Beyond neurodegeneration: Systemic confounders of blood neurofilament light chain in aging and their implications for neurological biomarker interpretation.

Unlike younger populations, older individuals often live with multiple systemic conditions that may influence neurofilament light chain (NfL) levels beyond true neuroaxonal injury, complicating its interpretation as a pure marker of neuronal damage. While prior work has examined determinants of blood NfL, none has specifically addressed its contextualization in the geriatric multimorbid setting. This narrative review critically examines the main non-neurological determinants of circulating NfL in older adults focusing on age, renal function, BMI, glycemic dysregulation, cardiovascular disease, and chronic hypoxia and discussing their clinical implications. Renal dysfunction and BMI appear to act as pharmacokinetic modifiers, altering NfL concentrations through reduced clearance and plasma volume dilution, respectively, without necessarily reflecting increased neuronal injury. In contrast, aging, dysglycemia, cardiovascular disease, and hypoxia may function as biologically active confounders, potentially contributing to neuroaxonal damage through neuronal attrition, microvascular injury, cerebral hypoperfusion, and oxidative stress. This distinction carries clinical implications: pharmacokinetic confounders call for adjusted reference ranges, while biologically active confounders represent true sources of neurological vulnerability warranting independent attention. Blood NfL levels in the geriatric population mirror complex neuro-systemic interactions requiring an integrated interpretive approach. Longitudinal monitoring and elderly-specific multivariate models could improve NfL's reliability as a tool in geriatric neurology.