Anticholinergic drugs and dementia: time for transparency in the face of uncertainty

Anticholinergic drugs which act on the cholinergic pathways are commonly used in clinical practice for management of conditions affecting old persons.

Some examples are, First generation anti-histamines diphenhydramine, chlorpheniramine used in cough medications, tricyclic antidepressants such as amitriptyline, Oxybutynin and tolterodine for urge incontinence and detrusor hyperactivity, oxybutynin for off label hyperhidrosis, tiotropium for COPD, cyproheptadine for stimulation of appetite.

The cumulative anticholinergic effect of all the medications a person takes is referred to as the ‘anticholinergic burden’ (ACB) because of its potential to cause adverse effects.

As with all drugs, in addition to therapeutic effects there will also be adverse effects – “Show me a drug with no side effects and I’ll show you a drug with no effect” (Professor Sir Derrick Dunlop). In the case of anticholinergic drugs, some adverse effects are short‐term (e.g. dry mouth, constipation) whereas others may be insidious and irreversible – one such concern related to long‐term ACB is a possible contribution to cognitive decline and dementia.

Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome
A Cochrane Review by Taylor‐Rowan et al determined whether anticholinergic burden, defined by recognized scales, is a prognostic factor for future cognitive decline or dementia in cognitively unimpaired older adults. They identified 25 studies, 20 of which were longitudinal cohort studies in community settings. With 968,428 participants in total, age range was 52 to 83 years, largely representative of the ‘older adult’ population. ACB was most frequently assessed using the ACB Scale, and the method for assessing the outcome measure of dementia or cognitive decline varied widely across the studies. Meta‐analysis suggested a possible doubling of the risk of dementia with anticholinergic drug exposure and that greater ACB increases the risk of dementia.
Cochrane Database of Systematic Reviews

All data in the review were obtained through observational studies, limiting our ability to move beyond mere associations to explore causality. Randomized controlled drug trials are predominantly designed to demonstrate drug efficacy, rather than safety. The reporting of adverse effects is variable, which makes it difficult to combine these important outcomes in meta‐analyses, and clear reporting of adherence is rare.

It will probably be several years before we have randomized controlled trial evidence to help us understand whether and how much ACB directly contributes to cognitive decline and dementia in older people.

Shared decision‐making, a key feature of high‐quality healthcare, requires explanation of potential risks and benefits of the treatment options. Many people see dementia as a worst‐case scenario. We should not ignore its potential association with ACB until causation is definitively demonstrated. A safety‐first approach, such as seen with alcohol intake and pregnancy, may be appropriate. Our patients expect transparency. How many people would choose a treatment option that might double their risk of developing dementia? In addition, some anticholinergic medication prescriptions, possibly 30% to 50% of antidepressant prescriptions, do not have evidence‐based indications and long‐term benefits are uncertain.


Clinicians should think carefully about the need to prescribe anticholinergic drugs to adults. Estimates suggest as many as 20% to 50% of older people are prescribed at least one anticholinergic medication. If the observed link between anticholinergic drug use and future dementia is causal, these exposure rates imply anticholinergics meaningfully contribute to the global dementia burden; albeit the extent of this contribution is difficult to determine due to the risk of bias present within studies. Moreover, there are associations with increased risk of mortality, impaired physical function, and reduced quality of life, emphasising the potential dangers anticholinergic drugs pose to older adults.

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