Cassie was just two weeks away from her 68th birthday as she sat in her doctor’s office presenting with symptoms that were consistent with severe dementia. Her daughter, Pat, told the doctor that her mom was always a very active woman, so seeing her mom deteriorate so quickly was shocking to her and the entire family.
From a health standpoint, especially when compared to many friends in her age group, Cassie had just a few medical issues -- seasonal allergies and itching for which she took Benadryl, Detrol for urinary incontinence, and a small amount of Trofinal for some mild mood changes. She never smoked, avoided excessive alcohol use, and until recently, always tried to eat right.
Her doctor, puzzled by the rapid onset of symptoms given her relatively unremarkable medical history, reached out to some of the prominent gerontologists in the Providence area. After several phone calls, testing, and multiple consultations, it was agreed that Cassie's cognitive decline was not the result of dementia but directly related to the medications she was taking.
Acetylcholine Is The Key
It appeared that her combination of prescriptions ended up blocking an important neurotransmitter in her brain called acetylcholine, which is vital for memory function. These drugs, known as anticholinergics, keep acetylcholine from binding to receptors on specific nerve cells, inhibiting the parasympathetic nerve impulses.
The parasympathetic nervous system is responsible for dilating blood vessels and regulating muscle contractions, bodily secretions, heart rate, among other important functions. In the brain, acetylcholine is responsible for attention span, concentration, and the formation of memories and consolidation (a time-dependent process by which newly learned experiences are transformed into long-term memory, presumably by structural and chemical changes in the nervous system).
The medications that Cassie was taking had anticholinergic properties, some strong, others less so, but combined they spelled trouble for her. Medications in this class include antidepressants such as imipramine (Tofranil, which Cassi was taking), antihistamines such as hydroxyzine (Vistaril), antipsychotics such as clozapine (Clozaril), antispasmodics like dicyclomine (Bentyl), and urinary incontinence medications such as tolterodine (Detrol).
In addition to these prescription medications, there are many over-the-counter drugs that have anticholinergic properties as well. These include antihistamines containing diphenhydramine like Benadryl, Chlor-Trimetron, and sleep aids like Tylenol PM, Aleve PM, and Nytol.
These drugs are widely used across all age groups to relieve the symptoms of seasonal or contact allergies, the common cold, hypertension, sleep disorders, or other reasons, but for older adults, anticholinergics are fraught with danger.
In a December 2020 story published in Neurology, an online magazine, researchers at the University of California San Diego School of Medicine have found that in seniors, there is an increased risk of cognitive decline, placing them at greater risk for the development of Alzheimer's disease.
In the study, the authors found that cognitively normal study participants taking at least one anticholinergic drug at baseline were 47% more likely to develop mild cognitive impairments, which is a precursor to dementia. These participants were tracked for up to ten years and compared to the control group who did not use any of these medications.
There were a total of 688 adults who took part in the study, evenly divided by sex with an average age of 74. None of the participants displayed any cognitive or memory issues at the beginning of the study. One-third of the participants were taking anticholinergic drugs, on average 4.7 per person. All study participants were given annual comprehensive cognitive tests during the span of the research.
Lisa Delano-Wood, Ph.D., senior author of the study, said that the outcome suggested that "reducing anticholinergic drug use before cognitive problems appear may be important for preventing future negative effects on memory and thinking skills, especially for people at greater risk for Alzheimer's disease."
Those taking anticholinergic medications and presenting with a genetic risk for developing Alzheimer's were nearly 2.5 times more likely to develop mild cognitive impairment than those without the genetic risk factors and not taking these medications.
Genetics and Anticholinergics
So what does this mean? In a nutshell, if you have a strong genetic risk factor in your family for Alzheimer's, and have a history of anticholinergic drug use appear to have a higher risk of developing dementia (it is important to note, however, that association does not equate to proof).
Dr. Weigland, the leader of the research group, stated, "we believe this interaction between anticholinergic drugs and Alzheimer's risk biomarkers acts in a 'double hit' manner. In the first hit, the [genetic] biomarkers indicate that pathology has started to accumulate in and degenerate a small region called the basal forebrain that produces the chemical acetylcholine, which promotes thinking and memory. In the second hit, anticholinergic drugs further deplete the brain's store of acetylcholine. This combined effect significantly impacts a person's thinking and memory."
So do anticholinergic medications affect all age groups equally? It appears it does not, at least to this point, given the fact that older adults metabolize medications in a much different way than do younger individuals. However, what stood out in this study was the fact that anticholinergic medications were being taken in much higher amounts than the lowest effective dose recommended for seniors, with "57% taken at twice the recommended dosage and 18% at least four times the recommended dosage" according to the study. Because of this, there is a wild card present -- is it dosage, number and combination of anticholinergic medications, or age that determines risk or a combination of the aforementioned? The research continues into this.
But in real numbers, it is estimated that at least 25% of older adults, that's 1 in 4, are taking some form of anticholinergic drugs, from medications used to treat allergies, insomnia, leaky bladders, diarrhea, dizziness, motion sickness, asthma, Parkinson’s disease, chronic obstructive pulmonary disease, and various psychiatric disorders.
The American Geriatrics Society Beers Criteria (a compendium of medications potentially to avoid or consider with caution because they often present an unfavorable balance of benefits and harms for older people) has a list of anticholinergic medications that are potentially inappropriate for seniors. And although gerontologists and those working in long term care facilities are aware of the AGS Beers Criteria, not all medical providers seeing older adults in the community are aware of the effects of anticholinergic medications and the rate at which they are being combined by their older patients who often don't see the use over-the-counter medications as something to be concerned enough about to tell their physicians.
Awareness for Decades
Awareness of the effects of anticholinergic drugs is not new as research on these medications actually began in the 1970s. But with the graying of America and a larger reliance on prescription and over the counter medications, concerns began to mount in the mid-2000s when multiple studies started to show that anticholinergic medications appeared to have a cumulative effect that resulted in the death of brain neurons and the accumulation of plaques and tangles (the difference between the plaques and tangles lies in their structure and effect on the nerve cells in the brain tissues. Amyloid plaques are clusters that form in the spaces between the nerve cells, whereas the neurofibrillary tangles are a knot of the brain cells) associated with neurodegeneration.
Another piece of research discussed in JAMA Internal Medicine also highlighted the association between anticholinergics and an elevated risk of dementia. This report discussed the results of a study done in Britain with 284,000 adults aged 55 and older. It found that more than half of the study participants had been prescribed at least one of 56 anticholinergic drugs (some had multiple prescriptions of these medications). Those who took a daily dose of a strong anticholinergic for three years had a 49% increased risk of dementia. Effects were most pronounced for people who took anticholinergic antidepressants, antipsychotics, antiepileptic drugs, and bladder control medications.
Although taking these medications have not yet been proven to cause dementia, there does exist a strong association. And ongoing research continues to suggest that older adults who take strong anticholinergic medications for one to three years are vulnerable to long-term side effects, including the onset of dementia type symptoms.
In our next blog, we will look at benzodiazepines and how this class of prescription medication has also been strongly associated with the onset of Alzheimer's disease and other types of dementia as well as being responsible in numerous cases of mistaken diagnoses.
Click on the photo below to download a copy of anticholinergic drugs that should be avoided by seniors. This list is from Drugs.com.