Abstract
AIMS: Anticholinergic drugs (ACDs) and the neurodegeneration biomarker neurofilament light chain (NfL) are associated with dementia; however, the interplay between anticholinergic drug exposure and neurodegeneration in dementia risk remains underexplored. METHODS: This prospective cohort study analyzed 1529 dementia-free adults (median follow-up 5.2 years) from the Shanghai Aging Study. Cumulative anticholinergic burden was quantified using the anticholinergic cognitive burden (ACB) scale and total standardized daily dose (TSDD) over 1 year pre-baseline. Neurofilament light chain (NfL) levels were assayed via single-molecule array (Simoa). RESULTS: Elevated NfL (adjusted HR 1.77, 95% CI, 1.07-2.92) and TSDD exposure (HR 1.55, 1.08-2.24) were independently associated with incident dementia risk. Participants with both TSDD exposure and high NfL levels showed substantially greater cumulative dementia incidence versus those with no TSDD/low NfL (log-rank p < 0.0001; adjusted HR 2.24, 1.20-4.20). Individuals with both high TSDD and high NfL demonstrated a significantly higher dementia risk (HR 6.34, 95% CI, 1.90-21.20) compared to low-burden counterparts. CONCLUSIONS: These findings identify plasma NfL as a critical modifier of anticholinergic-related cognitive vulnerability, providing mechanistic insights for risk stratification and supporting biomarker-guided deprescribing strategies in older adults exposed to ACDs.