Dual risk of anticholinergic burden and CSF alzheimer's biomarkers in older patients: a mortality follow-up study from daily medical practice.

Background: Anticholinergic medications are widely prescribed to older adults and are linked to increased mortality and cognitive decline. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD)-amyloid and tau-are strong prognostic indicators in neurocognitive disorders (NCD). However, it remains unclear whether anticholinergic burden amplifies mortality risk depending on CSF biomarker profiles in cognitively impaired individuals.

Methods: We conducted a retrospective monocentric study of 927 patients aged ≥ 65 years with mild or major NCD from a tertiary memory clinic in Paris, France. Participants underwent CSF biomarker assessment for amyloid (A), phosphorylated tau (T), and total tau (N), and were classified into ATN profiles. Anticholinergic burden was evaluated at baseline using the Anticholinergic Cognitive Burden (ACB) scale: none (ACB = 0), low-moderate (ACB = 1-2), or high (ACB ≥ 3). The primary outcome was all-cause mortality. Proportional hazards regression assessed associations between ACB, ATN profiles, and mortality, adjusting for demographic, clinical, and genetic covariates.

Results: High ACB was associated with increased mortality in model 1 (HR = 1.30, 95% CI: 1.03-1.64, p = 0.02), but not after full adjustment (HR = 1.26, 95% CI: 0.96-1.66, p = 0.09). ATN profiles remained strong independent predictors of mortality, with highest risks for A-T-N + and A + T + Nx profiles. Combined high ACB and abnormal biomarkers conferred greater risk than either alone (e.g., HR = 2.24 for A + T + Nx and high ACB).

Conclusion: Anticholinergic burden may increase vulnerability to mortality in older adults with an AD biomarker profile. These results support integrating pharmacological and biological risk factors into personalized dementia care.