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. 2025 Dec;31(12):e70691.
doi: 10.1002/cns.70691.

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

Danyi Chi  1 , Xiaoniu Liang  2   3   4 , Zhenxu Xiao  2   3   4 , Xiaowen Zhou  2   3   4 , Qianhua Zhao  2   3   4 , Bin Wang  1 , Ding Ding  2   3   4
Affiliations

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

Danyi Chi et al. CNS Neurosci Ther. 2025 Dec.

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.

Keywords: anticholinergic drugs; cohort study; dementia; neurodegeneration burden; neurofilament light chain; older adults.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
The distribution of blood NfL concentrations between participants with no TSDD and participants with TSDD. (P1) Univariate analysis of the NfL concentrations between participants with no TSDD and participants with TSDD. (P2) Comparisons of the blood NfL concentrations between participants with no TSDD and participants with TSDD adjusted by age, sex, and APOE. APOE, ε4+, apolipoprotein E ε4 positivity; NfL, neurofilament light chain; TSDD, total standardized daily dose.
FIGURE 2
FIGURE 2
Accumulative dementia incidence in participants among low, medium, and high‐risk groups. Plasma NfL was binarized by the median. TSDD was binarized by zero and non‐zero. Low: low‐risk group, non‐TSDD and low NfL; Medium: medium‐risk group, non‐TSDD and high NfL or TSDD and low NfL; High: high‐risk group, TSDD and high NfL. NfL, neurofilament light chain; TSDD, total standardized daily dose.
FIGURE 3
FIGURE 3
Accumulative dementia incidence in participants with TSDD among the low, medium, and high‐risk groups. Plasma NfL and TSDD were both binarized by the median. Low: low‐risk group, low TSDD and low NfL; Medium: medium‐risk group, low TSDD and high NfL or high TSDD and low NfL; High: high‐risk group, high TSDD and high NfL. NfL, neurofilament light chain; TSDD, total standardized daily dose.
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