Differential Impact of Neurofilament Light Subunit on Cognition and Functional Outcome in Memory Clinic Patients with and without Vascular Burden

The neurofilament light (NF-L) subunit is mainly expressed in large-caliber myelinated axons, and elevated concentrations in the cerebrospinal fluid (CSF) are correlated with damage to white matter and subcortical regions. Because the correlation between NF-L and cognition and functional impairment is largely unknown, we investigated associations in patients (n = 622) with (n = 199) and without (n = 423) vascular burden in subjective cognitive impairment (SCI, n = 168), mild cognitive impairment (MCI, n = 261), and dementia (n = 193). Patients were staged according to disease severity and the presence/absence of cerebrovascular disease. CSF amyloid-β(1-42) (Aβ(1-42)) was included in all models due to its concomitant influence on vascular and primary etiology. Linear regression was used to assess associations between NF-L and Aβ(1-42) and five cognitive domains of a comprehensive neuropsychological battery as well as with functional impairment using the Clinical Dementia Rating. Changes in these outcomes at the 2-year follow-up were also evaluated. In SCI and MCI patients with vascular burden, higher NF-L concentrations were associated with baseline cognitive performance (β = -0.38 to -0.58) and executive decline (β = -0.44). Lower Aβ(1-42) levels were associated with worse cognitive performance in dementia (β = 0.46 to 0.51). In MCI and dementia patients without vascular burden, higher NF-L (β = -0.30 to -0.34) and lower Aβ(1-42) concentrations (β = 0.30) were associated with reduced cognitive performance. Higher NF-L concentrations (β = -0.26) were associated with functional decline in patients with vascular burden. CSF NF-L is associated with cognition in patients with and without vascular etiology. These associations were greater in pre-dementia phases in those with vascular etiology and vice versa in those without vascular burden.