Anticholinergics Increase Dementia Risk in Middle-Aged, Older Adults

Julia Hippisley-Cox, MD

Patients 55 or older who take anticholinergic drugs daily face increased risk of dementia, according to a new study.

The nested case-control study drew from England’s QResearch primary care database to compare odds ratios (ORS) of dementia between 58769 patients diagnosed with dementia and 225574 controls. All included patients were 55 years or older (mean age 82.2), and 179365 (63.1%) were female. Each patient with dementia was matched to 5 controls by age (within a year,) sex, general practice, and calendar time via incidence density sampling.

All subjects of analysis took one of 56 anticholinergics daily and, if in the dementia group, had begun taking the drugs 1-11 years prior to diagnosis. Primary exposure was tracked in total standardized daily doses (TSDDs). Adjustments were made to the data to account for population-attributable fractions, protopathic bias, and additional variables such as patients with high BMI or alcohol consumption.

Julia Hippisley-Cox, MD, professor of clinical epidemiology and general practice at University of Oxford, England, led the team of investigators. Analysis of compiled data continued from May 2016 through June 2018.

The lowest anticholinergic exposure category, total exposure of 1-90 TSDDs, saw an increase in the adjusted OR for dementia from 1.06 (95% CI, 1.03-1.09). The highest category, >1095 TSDDs, increased to an OR of 1.49 (95% CI, 1.44-1.54). Both categories’ associations with dementia increased even further in patients who were diagnosed before age 80.

On the other hand, relevant antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinic drugs, and antiepileptic drugs all didn’t demonstrate any significant increases in dementia risk.

An editorial accompanying the study noted that despite the proven mechanistic link between anticholinergic drugs and dementia diagnosis, further research was vital to prove causation altogether. The editorial also recommended conducting deprescribing trials to consider the harms of ceasing anticholinergic treatments for fear of an increased dementia risk. Furthermore, what is the time window when ceasing anticholinergic medications could still benefit the patient?

These and other questions, the editorial emphasizes, necessitate further studies.

“We propose deprescribing research as a high priority in the effort to reduce the burden of ADRD (Alzheimer disease and related dementias), while also learning about efficient and safe approaches to optimize medication use in older adults,” the editorial said.

Previous studies throughout the past several years have stoked similar fears about anticholinergic drugs and their use in older patients. In a 2016 study of older patients (mean age 73.3 years) using anticholinergic medications, brain scans and cognitive tests indicated both physical and physiological manifestations of reduced brain function.

Even earlier, a 2015 study demonstrated an increased risk of dementia and Alzheimer’s disease in patients 65 or older who took anticholinergic medications regularly (usually antidepressants, first-generation antihistamines, or bladder control antimuscarinics).

As evidence of the association between anticholinergics and dementia mounts, medical practitioners may be forced to reconsider the benefits of prescribing such drugs to middle-aged or older adults in light of the risks. Further research ought to further illuminate whether association does in fact indicate causation.

The study, “Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study,” was published by JAMA Internal Medicine.