Drugs That Block “Vagusstoff” May Speed Up Cognitive Decline

Anticholinergic medications may increase Alzheimer’s risk, a new study reports.

Posted Sep 07, 2020

BruceBlaus/Wikimedia Commons
Acetylcholine (ACh) pathway.
Source: BruceBlaus/Wikimedia Commons

Anticholinergic medications block acetylcholine (i.e., "vagusstoff") and inhibit parasympathetic nerve impulses by binding with this neurotransmitter's receptors. Over 600 medications are known to trigger some degree of anticholinergic activity (Ghossein, Kang, & Lakhkar, 2020).

Anticholinergics are a common class of drugs prescribed by doctors—or purchased over-the-counter (OTC) without a prescription—for the treatment of allergies, asthma, common cold symptoms, COPD, hay fever, hypertension, overactive bladder, Parkinson's disease as well as psychiatric disorders, depression, and a host of other ailments.

What Is Acetylcholine and Why Is It Also Called "Vagusstoff"?

Acetylcholine (ACh) was the first neurotransmitter ever discovered by scientists. In 1921, a German-born psychobiologist and pharmacologist, Otto Loewi (1873-1961), identified a substance secreted by the vagus nerve that slowed heart rate. He named this stuff "vagusstoff," which is German for "vagus nerve substance." (See "How Does 'Vagusstoff' (Vagus Nerve Substance) Calm Us Down?") 

By the mid-20th century, vagusstoff was more commonly referred to as acetylcholine. Scientists of this era also determined that ACh mediates how the autonomic nervous system's parasympathetic branch counterbalances "fight-or-flight" stress responses.

In the 1970s, neuroscientists discovered that acetylcholine crosses the blood-brain barrier (Cornford & Oldendorf, 1975) and works differently in the central nervous system, which includes the brain and spinal cord. As a chemical messenger in the brain, acetylcholine pathways are vital to cognitive performance and memory function.

About five years ago, pharmacologists (Aberra et al., 2015) and public health advocates began to warn older adults about using medications with strong anticholinergic properties because these drugs appeared to have some adverse neurocognitive side effects.

Around this time, a prospective cohort study (Gray et al., 2015) on the cumulative use of strong anticholinergics and incident dementia 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."

Now, a new study (Weigand et al., 2020) led by researchers from the University of California, San Diego, reports that anticholinergic medications may be linked to a higher incidence of mild cognitive impairment (MCI) among cognitively normal older adults and may increase Alzheimer's disease risk. These findings were published on September 2 in the journal Neurology.

The objective of this study was "to determine the cognitive consequences of anticholinergic medications in cognitively normal older adults as well as interactive effects of genetic and cerebrospinal fluid (CSF) Alzheimer's disease risk factors." 

Of the 688 men and women who participated in this study, the researchers reported that over the course of a decade, those who regularly used at least one anticholinergic drug at baseline were 47 percent more likely to develop mild cognitive impairment (MCI) than study participants who did not take ACh-blocking medicines.

Additionally, Weigand et al. found that participants who were taking anticholinergic drugs and had biomarkers associated with a higher risk for Alzheimer's disease in their cerebrospinal fluid were four times more likely to develop MCI than participants lacking these biomarkers and not taking anticholinergics.

"This study, led by Alexandra Weigand, suggests 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," senior author Lisa Delano-Wood said in a news release

"We believe this interaction between anticholinergic drugs and Alzheimer's risk biomarkers acts in a 'double hit' manner," Weigand added. "In the first hit, Alzheimer's 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 most significantly impacts a person's thinking and memory."

The authors note that about 57 percent of participants in this study using anticholinergics took twice the recommended dosage and 18 percent of people who used these medications took about four times the recommended dosage for older adults.

This UCSD-led study reaffirms the importance of asking your doctor* about the pros, cons, and appropriate dosage of any medication you're taking that has anticholinergic properties.

"This points to a potential area for improvement since reducing anticholinergic drug dosages may possibly delay cognitive decline," Weigand said. "It's important for older adults who take anticholinergic medications to regularly consult with their doctors and discuss medication use and dosages."

Delano-Wood acknowledges that more research "is needed to examine brain and cognitive effects of anticholinergic medications and whether these medications accelerate age-related cognitive changes or directly lead to neurodegenerative disorders, such as Alzheimer's disease."

The next step is for researchers around the country who are participating in a series of randomized clinical "deprescribing" studies to gather more empirical evidence pertaining to the hypothesis that curbing the use of anticholinergics may curtail the incidence of MCI in healthy adults and decreases Alzheimer's risk in vulnerable populations.

Here's a list of anticholinergic drugs from April 2020 that also explains why some of these medications may be dangerous for seniors.

*DISCLAIMER: This article is not intended as medical advice. Always consult with your doctor about the appropriate dosage and potential adverse side effects of any anticholinergic medication you are prescribed or purchase without a prescription over the counter.

References

Alexandra J. Weigand, Mark W. Bondi, Kelsey R. Thomas, Noll L. Campbell, Douglas R. Galasko, David P. Salmon, Daniel Sewell, James B. Brewer, Howard H. Feldman, Lisa Delano-Wood. "Association of Anticholinergic Medication and Alzheimer's Disease (AD) Biomarkers With Incidence of Mild Cognitive Impairment (MCI) Among Cognitively Normal Older Adults." Neurology (First published online: September 02, 2020) DOI: 10.1212/WNL.0000000000010643

Shelly L. Gray, Melissa L. Anderson, Sascha Dublin, Joseph T. Hanlon, Rebecca Hubbard, Rod Walker, Onchee Yu, Paul K. Crane, Eric B. Larson. "Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study." JAMA Internal Medicine (First published online: January 26, 2015) DOI: 10.1001/jamainternmed.2014.7663