What was the aim of this review?
Medicines can be classified by their ability to block the action of a chemical signalling system in the body called the cholinergic system. Medicines that do this are said to have anticholinergic effects. There are various measurement scales to quantify the effects of anticholinergic medicines. The overall anticholinergic effect caused by all the anticholinergic medications a person is taking is referred to as 'anticholinergic burden.'
We aimed to investigate if older people who have no problems with memory or thinking are more likely to develop dementia when prescribed anticholinergic medicines than people who are not prescribed these medicines.
Anticholinergic burden ratings can vary with the scale used because different scales score medicines in different ways. Therefore, we also wanted to know if any particular anticholinergic burden measurement scale was more strongly associated with increased risk of dementia than other scales.
Key messages
There may be a link between anticholinergic medicine use and future risk of dementia. However, there are limitations in the published evidence, and we cannot say definitively if dementia is caused by the anticholinergic medicines themselves or by other factors. There were too few studies to allow us to compare the various anticholinergic measurement tools.
What was studied in the review?
There are more than 40 million older people worldwide living with dementia. These numbers are expected to rise to over 100 million by 2050 and at present there are very limited treatment options available. Therefore, it is important to identify factors that may increase the risk of dementia.
Because the cholinergic system in the brain plays an important role in learning and memory, there are theoretical reasons to believe that medications with anticholinergic effects could cause future dementia. Research has suggested that these medications may have unintended effects on memory and thinking, potentially resulting in dementia. If this is the case, one way to reduce the numbers of older people who develop dementia may be to avoid prescribing these medicines. Many commonly used medications have anticholinergic effects, for example medications for hay fever, insomnia (difficulty getting to sleep or staying asleep for long enough to feel refreshed), and depression.
In this review, we investigated the link between anticholinergic medicines, as measured by various measurement scales, and future dementia.
What were the main results of the review?
We found 25 studies, including 968,428 people aged 50 years or more. Despite the relatively large number of studies, differences in design and methods only allowed us to combine a few of them in analyses. We found that there is a consistent link between use of anticholinergic medicines and risk of future dementia. We cannot say if these medicines play a causal role; however, if they do, taking these medicines could potentially double a person's risk of dementia.
Of the anticholinergic measurement scales available, we could assess one commonly used tool – the 'Anticholinergic Cognitive Burden scale.' If this scale identified someone as having high anticholinergic burden, the risk of future dementia was more than two times higher than for someone with no anticholinergic burden.
The evidence included in this review was of a low quality overall and may have exaggerated the strength of the association between anticholinergic medicines and dementia. For example, anticholinergic medicines may be prescribed for the early symptoms of dementia. This would give a strong link but would not imply that the medicine caused the memory problems. Similarly, there is a risk that studies are only published when they show an association between anticholinergic medicines and future dementia. It may be that the only way to truly establish if anticholinergic medications are associated with future dementia would be to conduct a study where some people have their anticholinergic medications stopped or changed to an alternative and others continue their usual medications.
How up to date was this review?
We searched for studies published up to 24 March 2021.
There is low-certainty evidence that older adults without cognitive impairment who take medications with anticholinergic effects may be at increased risk of cognitive decline or dementia.
Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the 'anticholinergic burden' because of its potential to cause adverse effects. It is possible that high anticholinergic burden may be a risk factor for development of cognitive decline or dementia. There are various scales available to measure anticholinergic burden but agreement between them is often poor.
To assess whether anticholinergic burden, as defined at the level of each individual scale, is a prognostic factor for future cognitive decline or dementia in cognitively unimpaired older adults.
We searched the following databases from inception to 24 March 2021: MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), and ISI Web of Science Core Collection (ISI Web of Science).
We included prospective and retrospective longitudinal cohort and case-control observational studies with a minimum of one year' follow-up that examined the association between an anticholinergic burden measurement scale and future cognitive decline or dementia in cognitively unimpaired older adults.
Two review authors independently assessed studies for inclusion, and undertook data extraction, assessment of risk of bias, and GRADE assessment. We extracted odds ratios (OR) and hazard ratios, with 95% confidence intervals (CI), and linear data on the association between anticholinergic burden and cognitive decline or dementia. We intended to pool each metric separately; however, only OR-based data were suitable for pooling via a random-effects meta-analysis. We initially established adjusted and unadjusted pooled rates for each available anticholinergic scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales. We examined variability based on severity of anticholinergic burden.
We identified 25 studies that met our inclusion criteria (968,428 older adults). Twenty studies were conducted in the community care setting, two in primary care clinics, and three in secondary care settings. Eight studies (320,906 participants) provided suitable data for meta-analysis. The Anticholinergic Cognitive Burden scale (ACB scale) was the only scale with sufficient data for 'scale-based' meta-analysis. Unadjusted ORs suggested an increased risk for cognitive decline or dementia in older adults with an anticholinergic burden (OR 1.47, 95% CI 1.09 to 1.96) and adjusted ORs similarly suggested an increased risk for anticholinergic burden, defined according to the ACB scale (OR 2.63, 95% CI 1.09 to 6.29). Exploratory analysis combining adjusted ORs across available scales supported these results (OR 2.16, 95% CI 1.38 to 3.38), and there was evidence of variability in risk based on severity of anticholinergic burden (ACB scale 1: OR 2.18, 95% CI 1.11 to 4.29; ACB scale 2: OR 2.71, 95% CI 2.01 to 3.56; ACB scale 3: OR 3.27, 95% CI 1.41 to 7.61); however, overall GRADE evaluation of certainty of the evidence was low.