I’ll never forget the time Granddaddy tried to eat my hand. At least that’s how it seemed to me at age six. In reality, he’d simply confused my hand with the straw sticking out of the milkshake we’d brought to him at the nursing home. By that point in his early-onset Alzheimer’s disease, the Granddaddy I’d known and loved was long gone.
Alzheimer’s disease is the most common form of dementia. It can be inherited as a clearly identifiable genetic disorder, as in my grandfather’s case. More often, it results from a combination of events that are poorly understood except in terms of risk factors, such as family history, stroke, head injury, hypertension, heart disease, and diabetes.
A growing body of evidence suggests that long-term use of some very common medications may also play a role. Most people, including medical providers, are unaware of this. Many drugs have anticholinergic effects, and although most people are unfamiliar with the term, you likely have at least one bottle of anticholinergic medication ¹ in your medicine cabinet. It is not unusual for people to take more than one drug of this type on a regular basis.
Anticholinergic drugs block receptors for the neurotransmitter acetylcholine (ACh), which prevents the receptors from being activated. To illustrate, think of somebody putting glue into a keyhole, and then imagine trying to unlock the door. Sometimes the anticholinergic effect is directly related to the therapeutic action of the drug, and sometimes it is merely a side effect. Anticholinergic medications are used to treat a broad range of symptoms and conditions and include such well-known brands as Paxil, Benadryl, Unisom, Nyquil, Dramamine, and Zantac.
There are many more examples of these drugs in widespread use, especially among elderly patients, for things like nausea, overactive bladder, gastroesophageal reflux disease, and chronic obstructive pulmonary disease. The most recent estimates are that somewhere between 10% and a quarter of community-dwelling Americans over age 65 take at least one drug with anticholinergic activity regularly, despite longstanding recommendations against their use in seniors. Use of these drugs is even more common among nursing home patients with dementia.
Impaired cognition and memory problems are well-known side effects of anticholinergic medications, especially in geriatric patients. Use of these drugs has also been associated with increased cognitive decline in older individuals, and drugs like donepezil (aka Aricept) used to treat dementia symptoms, actually work by boosting ACh levels. The results of several recent epidemiological studies suggest that long-term use of anticholinergic medications may in fact promote the development of dementia. Three particularly compelling papers are described in greater detail below.
The first, published in 2003 in Annals of Neurology, examined the relationship between anticholinergic drugs and postmortem neuropathology in Parkinson’s patients who had shown no overt signs of dementia prior to death. The authors found a strong association between anticholinergic use and Alzheimer’s-like brain abnormalities. Of particular note is that the degree of Alzheimer’s-like pathology was correlated with cumulative anticholinergic exposure; the longer patients took anticholinergic drugs, the more their brains resembled those of typical Alzheimer’s patients.
A second study was published in JAMA Internal Medicine in March 2015 and followed 3400 participants aged 65 and older who were initially free from dementia over a 10-year period. The researchers used pharmacy records to track medication use, and the total number of single standardized daily doses of anticholinergic medication was determined for each patient. Regardless of whether anticholinergic drugs were taken sporadically over longer periods or more frequently for shorter durations, the more total doses a person took, the more likely he or she was to develop dementia. Patients who took a single daily dose of a medication comparable to Benadryl (in terms of anticholinergic activity) for 3-12 months exhibited a 19% higher risk of dementia relative to patients who did not take anticholinergics, with the elevated risk increasing to 23% with 1-3 years’ use, and to 54% beyond that.
The most recent study to indicate a link between anticholinergic medications and incident dementia was published in April 2016 in JAMA Neurology and included 451 initially cognitively normal seniors. Patients underwent brain scans and cognitive function tests, and those who regularly took moderate to strong anticholinergic drugs exhibited decreased brain volume, poorer cognitive performance, and increased odds of progression to an Alzheimer’s diagnosis during the 2-year follow-up.
Experiments in laboratory animals provide additional evidence suggestive of a causal relationship between anticholinergic drugs and dementia. Blocking ACh transmission in mice, guinea pigs, and rabbits produces cellular and structural brain abnormalities similar to those of Alzheimer’s patients. In fact, experimentally decreasing ACh results in both amyloid plaques and neurofibrillary tangles – the hallmark features of Alzheimer’s – in animals.
Clinicians are often quick to assert that animal studies and human observational studies are inadequate to prove causation; that requires randomized controlled experiments in humans. True enough. But we can only act according to the best information we have at any given time, and failure to exercise appropriate caution here may well end up looking a lot like the tragic “debate” over whether tobacco really causes lung cancer.
There are effective alternatives for many, if not most, conditions that anticholinergic drugs are used to treat. We have ample evidence to warrant using these alternatives when feasible. Use of anticholinergic drugs in older people results not only in poorer patient outcomes but also in higher health care costs. What is needed now is greater public awareness about the potential risks of long-term use of these drugs and greater commitment among health professionals to adhere to established guidelines regarding their use.
I know it’s easy to disregard the information presented here. There’s a media story nearly every week about some awful new outcome linked to a medication. Most of us have learned to largely ignore these. But this is a case in which it is especially important to take the threat seriously. We are our brains. Proceed with caution, because the stakes could not be higher.
¹ The main text provides an embedded link to a paper with a composite scale for estimating the relative anticholinergic strengths of different drugs. Below are links to two additional practical resources:
- A simple, user-friendly “tool” based on the Anticholinergic Cognitive Burden Scale that allows a person taking multiple medications to calculate a total “cognitive burden” score and provides a description of the relationship between that score and odds of progressive cognitive impairment.
- The Anticholinergic Drug Scale, a table that provides a 1 to 3 rating for more than 80 anticholinergic drugs as well as a long list of drugs ranked “0” – meaning they have no measurable anticholinergic activity. The numerical rankings were based on expert consensus, but subsequent work confirmed that scores were highly correlated with serum anticholinergic activity, a more objective biochemical measure.