Anticholinergic Drugs and Incident Dementia, Mild Cognitive Impairment and Cognitive Decline

A Meta-analysis

Nina T. Pieper; Carlota M. Grossi; Wei-Yee Chan; Yoon K. Loke; George M. Savva; Clara Haroulis; Nicholas Steel; Chris Fox; Ian D. Maidment; Antony J. Arthur; Phyo K. Myint; Toby O. Smith; Louise Robinson; Fiona E. Matthews; Carol Brayne; Kathryn Richardson

Disclosures

Age Ageing. 2020;49(6):939-947. 

In This Article

Abstract and Introduction

Abstract

Background: the long-term effect of the use of drugs with anticholinergic activity on cognitive function remains unclear.

Methods: we conducted a systematic review and meta-analysis of the relationship between anticholinergic drugs and risk of dementia, mild cognitive impairment (MCI) and cognitive decline in the older population. We identified studies published between January 2002 and April 2018 with ≥12 weeks follow-up between strongly anticholinergic drug exposure and the study outcome measurement. We pooled adjusted odds ratios (OR) for studies reporting any, and at least short-term (90+ days) or long-term (365+ days) anticholinergic use for dementia and MCI outcomes, and standardised mean differences (SMD) in global cognition test scores for cognitive decline outcomes. Statistical heterogeneity was measured using the I 2 statistic and risk of bias using ROBINS-I.

Results: twenty-six studies (including 621,548 participants) met our inclusion criteria. 'Any' anticholinergic use was associated with incident dementia (OR 1.20, 95% confidence interval [CI] 1.09–1.32, I 2 = 86%). Short-term and long-term use were also associated with incident dementia (OR 1.23, 95% CI 1.17–1.29, I 2 = 2%; and OR 1.50, 95% CI 1.22–1.85, I 2 = 90%). 'Any' anticholinergic use was associated with cognitive decline (SMD 0.15; 95% CI 0.09–0.21, I 2 = 3%) but showed no statistically significant difference for MCI (OR 1.24, 95% CI 0.97–1.59, I 2 = 0%).

Conclusions: anticholinergic drug use is associated with increased dementia incidence and cognitive decline in observational studies. However, a causal link cannot yet be inferred, as studies were observational with considerable risk of bias. Stronger evidence from high-quality studies is needed to guide the management of long-term use.

Introduction

Dementia affects more than 40 million people with direct healthcare costs of $818 billion in 2015.[1] Dementia is characterised by irreversible and progressive cognitive impairment, with consequent disability and dependence. 'Cognitive impairment' itself refers to problems with cognitive abilities such as memory, problem solving, learning, perception and language. Cognitive impairments are common in the older population, with different aspects of cognition independently affected with age and by different neurological diseases.[2] While cognitive impairment does not always progress to dementia, it nevertheless presents a social and economic cost. A classification of 'mild cognitive impairment (MCI)' identifies those with cognitive impairments that are not severe enough to meet the definition of dementia.[3] Many different operational definitions of dementia, cognitive impairment and MCI are used in clinical and research contexts.

Identification of possible modifiable risk factors for dementia is paramount.[4] Some studies have suggested that anticholinergic medication use might be a modifiable risk factor for cognitive impairment or dementia.[5,6] Drugs with anticholinergic properties inhibit the action of acetylcholine at its receptor.[7] Such drugs have many indications,[7] including urinary incontinence and depression.[8] Short-term cognitive impairments are well-known side effects of anticholinergic drugs, but several recent observational studies suggest links to longer-term cognitive impairment and dementia incidence.[9–11] Around 10% of people aged 65 years and older regularly use strongly anticholinergic drugs.[12,13]

Several observational studies report an association between anticholinergic drug use and cognitive function;[9,10,14,15] however, the magnitude of effects and strengths of their study designs vary considerably.[16] A review conducted by the members of our study team identified 33 observational studies of cognitive effects of anticholinergics, with 23 studies reporting lower cognitive function among users.[16] However, this review did not include a meta-analysis, nor specifically consider long-term effects or risks of bias. A separate meta-analysis reported an association between anticholinergic use and dementia incidence but included only three cohort studies.[17] Larger and more carefully controlled observational studies have since been published addressing limitations of earlier work; hence a new quantitative systematic review is warranted.[9,10] The evidence regarding these relationships arises from non-randomised observational studies, which are subject to uncontrolled confounding, misclassification and selection bias. Hence a careful assessment of risk of bias is needed when interpreting individual or pooled study findings.

Here we report a systematic review and meta-analysis of the association between strongly anticholinergic drug use and subsequent cognitive decline, incident dementia and incident MCI, in older adults. We carefully assess risk of bias and the reasons for any heterogeneity in study findings.

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