Most pharmaceutical treatments for patients with Alzheimer disease (AD) target acetylcholine, with the goal of raising brain levels of this neurotransmitter. Does this mean that chronically decreasing acetylcholine levels could cause dementia?
Researchers at the University of Washington in Seattle have indicated this is possible. Their recent study demonstrated that anticholinergic use could confer an increased risk of dementia. The risk seemed to be dependent on the dose and the amount of use.
Several medications used to treat AD—including galantamine, rivastigmine, and donepezil—are designed to delay cognitive decline by acting to increase levels of the neurotransmitter acetylcholine. They do this by targeting acetylcholinesterase, the enzyme responsible for its breakdown. So it is not much of a reach to speculate that anticholinergic medications could have the opposite detrimental effects on cognition.
In fact, numerous medications (eg, antidepressants and antihistamines) have anticholinergic effects and can cause cognitive impairment. As a rule, anticholinergic-induced cognitive impairment can be reversed if the medication is discontinued. The researchers who conducted this study sought to understand whether anticholinergics could in fact increase dementia risk over time.
Led by Shelly Gray of that School of Pharmacy at the University of Washington in Seattle, the research group used data from the Adult Changes in Thought study in Group Health, a Seattle-based health care delivery system. The investigators included 3434 subjects who were age 65 years or older and who did not have dementia at the beginning of the study. They started collecting data in 1994 and included data through September of 2012.
The researchers used computerized pharmacy dispensing data to determine whether the study subjects had taken anticholinergic medications and how much over time. The measurements they took included medication dose, name, route of administration, date dispensed, and amount dispensed. The scientists also examined whether dementia and AD developed in the subjects using the Cognitive Abilities Screening instrument at the beginning of each one’s enrollment in the study and every 2 years afterwards.
Overall, the most frequently used medications with anticholinergic effects were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. Dementia developed in a total of 797 participants; 637 of the 797 cases were AD.
There was a statistically significant relationship between dementia and AD and the dose of anticholinergic medication taken. When comparing use of an anticholinergic with no use, the risk of both AD and dementia increased significantly.
The investigators concluded, “Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.”
They noted that prescribers might want to consider carefully whether to give anticholinergic medications to older patients, stating, “Prescribers should be aware of this potential association when considering anticholinergics for their older patients and should consider alternatives when possible.”
The group plans to further study anticholinergic use and its effects. Lead author Shelly Gray told Neurology Times, “With regard to future directions, we will be examining the relationship between anticholinergic use and brain pathology in a subset of this study cohort that has had autopsies performed.”
Dr Gray offered the following suggestions and interpretations:
• Older adults should not stop taking any anticholinergic medications that are recommended by their health care provider but instead should discuss the risks vs the benefits of continued therapy.
• Older adults should be aware that many medications—including some available over-the-counter drugs, such as sleep aids—have strong anticholinergic effects. Older adults can ask their pharmacist and prescribers about how to avoid over-the counter medications that have strong anticholinergic effects.
• Older adults are advised to inform their health care providers of all over-the counter medication use so that the providers can account for all anticholinergic medications and advise on how, if possible, to reduce use.
• For most conditions there are alternatives to anticholinergics, including nondrug measures for some. However, if anticholinergic therapy is warranted, health care providers should use the lowest effective dose, monitor the therapy regularly to ensure that it’s working, and stop the therapy if it’s ineffective.
The study was published online on January 26, 2015 in JAMA Internal Medicine.
• Anticholinergic medications increase the risk of dementia, including AD.
• The risk of dementia and AD increases with dose and chronic use of anticholinergics.
• This study may have implications for the use of anticholinergics in older adults.
1. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015 Jan 26. doi: 10.1001/jamainternmed.2014.7663. [Epub ahead of print]