Cerebrospinal fluid neurofilament heavy protein levels associated with domain-specific cognitive decline in Alzheimer’s disease

Abstract

Background Neurofilament proteins are fluid biomarkers of neuroaxonal damage in various neurological diseases. However, it remains to be elucidated whether CSF neurofilament heavy (NfH) protein levels correlate with cognitive decline and progression in Alzheimer’s disease (AD). Methods This study included 165 cognitively unimpaired (CU) participants, 385 participants with mild cognitive impairment (MCI), and 128 participants with AD. To examine correlations between CSF NfH levels and baseline cognitive measures, Pearson’s correlation was used. Linear mixed-effects models were fitted to assess the relationship between elevated CSF NfH levels and longitudinal cognitive decline in the CU, MCI and AD groups. Kaplan–Meier survival analyses and Cox proportional hazards models were used to assess the clinical progression in the CU and MCI groups separately. Results In the MCI group, higher CSF NfH levels were significantly associated with poorer performance across global measures (MMSE, CDR-SB, ADAS-Cog-13, and RAVLT immediate recall; p < 0.001) and three cognitive domains (such as memory, language, and executive function), in both cross-sectional and longitudinal analyses. In contrast, the significant associations in the CU and AD groups were observed for a subset of cognitive tests and domains. Kaplan–Meier survival analyses showed that the high CSF NfH group had higher progression rates than the low group in both the CU and MCI groups. In the Cox proportional hazards models, baseline CSF NfH (continuous) remained a significant predictor of clinical progression. Discussion Higher CSF NfH levels were associated with faster cognitive decline and clinical progression in CU and MCI groups but not in participants with AD, suggesting its potential as a biomarker for tracking early disease progression and cognitive impairment.