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. 2025 Oct 30;54(11):afaf326.
doi: 10.1093/ageing/afaf326.

The anticholinergic medication index and dementia risk: evidence from the UK Biobank and All of Us research program

Innocent Gerald Asiimwe  1   2 , Kate Best  3 , Reecha Sofat  1 , Oliver M Todd  3   4 , Lauren Walker  1 , Andrea L Jorgensen  2 , Andrew Clegg  3   4 , Munir Pirmohamed  1
Affiliations

The anticholinergic medication index and dementia risk: evidence from the UK Biobank and All of Us research program

Innocent Gerald Asiimwe et al. Age Ageing. .

Abstract

Introduction: Anticholinergic drugs are associated with adverse effects, including cognitive decline. In this study, we externally validated the Anticholinergic Medication Index (ACMI) by investigating the association between baseline anticholinergic burden and dementia risk in two large prospective cohorts: the UK Biobank (UKB) and the US All of Us (AoU) program.

Methods: We analysed data from the UKB (n = 125 260; study period, 2000-15) and AoU (92 047; 2000-22). Cox proportional hazards models, adjusted for clinical and genetic covariates with death as a competing risk, assessed the association between baseline annual ACMI-computed anticholinergic burden and dementia risk. Exploratory genetic analyses included candidate gene analysis of acetylcholine signalling pathway genes in the UKB and development of a polygenic hazard score in AoU.

Results: Prescription of any of the 88 ACMI-listed drugs at baseline was associated with increased dementia risk (UKB HR: 1.15, 95% CI 1.09-1.21; AoU: 1.06, 1.04-1.09) and mortality (UKB: 1.23, 1.19-1.27; AoU: 1.16, 1.13-1.19). We replicated the genetic influence of APOE on dementia risk (UKB [APOE ε4 vs ε3 carriers] HR: 2.05, 1.86-2.26; AoU: 1.61, 1.44-1.80). No significant gene-drug interactions were identified.

Conclusion: Higher baseline ACMI scores were associated with increased risks of dementia and mortality in two large cohorts, providing external validation of the ACMI. While causal inference is not possible, these findings support the ACMI's potential utility as a prognostic tool for risk stratification and for informing future work on safer prescribing.

Keywords: ACMI; All of Us Research Program; UK Biobank; anticholinergic burden; dementia; older people.

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Conflict of interest statement

The ACMI model equation and associated Code lists used to define variables are available for research use. ACMI will be available to suppliers of UK electronic health record systems, risk stratification software and for use in NHS policy and commissioning under the terms of an agreed licence agreement, including for organisations wishing to use ACMI for commercial purposes. MP has received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis). He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is part of the IMI Consortium ARDAT (www.ardat.org). None of these funding sources has been used for the current paper. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Flow chart for included participants. Bold values represent the total number of participants at each stage. aThis count excludes those who were additionally excluded due to discordant genetic and self-reported sex (n = 57), sex chromosome aneuploidy (n = 98) and being related to other included participants. (n = 3244).
Figure 2
Figure 2
Hazard ratios for the association between anticholinergic burden and dementia (death as a competing risk) in the UK Biobank (a) or death (b). To enable a direct comparison between the different scales and scale ratings, the anticholinergic burden as computed by each scale/rating was scaled to have a mean of 0 and a standard deviation of 1. All models were adjusted for age at index date, sex, data provider, ‘registration before 1 January 1999’ status, race, genotyping array, apolipoprotein A carrier status, prior comorbidities (depression, diabetes, hypercholesterolemia, hypertension and stroke) and the first two principal components of genetic ancestry. ACMI, Anticholinergic Medication Index; CI, confidence interval.
Figure 3
Figure 3
ACMI’s prediction of dementia (death as a competing risk) in the UK Biobank (a) and All of Us program (b). All models were adjusted for age at index date, sex, data provider, ‘registration before 1 January 1999’ status, race, genotyping array, apolipoprotein A carrier status, prior comorbidities (depression, diabetes, hypercholesterolemia, hypertension and stroke) and the first two principal components of genetic ancestry. ACMI, Anticholinergic Medication Index; CI, confidence interval.
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