Joint Effects of Anticholinergic Burden and Neurofilament Light on Dementia Risk: The Shanghai Aging Study

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.