Cognitive function in the context of pharmacogenetic CYP2D6 variability and anticholinergic burden in older adults – results from the ActiFE study

04/08/2026

AI Summary

CYP2D6 metaboliser status modifies the association between anticholinergic burden from CYP2D6 substrates and cognitive performance in older adults.
Intermediate metabolisers showed significant negative association with MMSE at the 75th percentile; effect strengthened after excluding CYP2D6 inhibitors.
Results for poor metabolisers were inconclusive due to small subgroup; pharmacogenetic data may aid individualised anticholinergic risk assessment pending longitudinal confirmation.

Eur J Clin Pharmacol. 2026 Aug 4;82(8):225. doi: 10.1007/s00228-026-04155-y.

ABSTRACT

PURPOSE: To investigate the role of CYP2D6 and its pharmacogenetic variability in the association between anticholinergic burden and cognitive function in older adults.

METHODS: We conducted a cross-sectional analysis of 872 community-dwelling adults ≥ 65 years from the ActiFE-Ulm cohort. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Anticholinergic burden scores deriving from CYP2D6-metabolised drugs (ABS_2D6) were calculated for all regularly scheduled medications. CYP2D6 metaboliser status was determined via genotyping and categorised as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM). The 25th, 50th, and 75th percentiles of the MMSE score distribution were studied using quantile regression to examine the association between ABS_2D6 and cognition, including interaction and stratified analyses by metaboliser status.

RESULTS: ABS_2D6 was significantly associated with lower MMSE scores at the 50th and 75th percentiles in early models, but not after additional adjustment for age and sex. A consistent effect modification by IM status was observed at the 75th percentile, with IMs showing a significant negative association between ABS_2D6 and MMSE in stratified analyses (β = -0.34 [95% CI: -0.64, -0.05]). After excluding participants with use of CYP2D6 inhibitors, this effect became more pronounced (β = -0.50 [95% CI: -0.82, -0.18]). Findings among PMs remained uncertain due to limited subgroup size.

CONCLUSION: These exploratory findings suggest that CYP2D6 metaboliser status may contribute to interindividual susceptibility to anticholinergic burden-related lower cognitive performance. If confirmed in larger longitudinal studies, pharmacogenetic information may support more individualised anticholinergic risk assessment and safer prescribing in older adults.

PMID:42547570 | DOI:10.1007/s00228-026-04155-y

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