Can anticholinergic medications increase the risk of mild cognitive impairment?

During my medical residency in neurology at the Hospital of Federal Fluminense University (UFF) in Rio de Janeiro/Brazil we often faced the following question: some medications commonly prescribed in routine neurology practice (for patients with Parkinson’s syndrome, depression or urinary alterations) inhibited the neurotransmitter acetylcholine, important for the formation and maintenance of memory. Since one of the proposals for the pharmacological treatment of Alzheimer’s disease is precisely to increase the concentration of acetylcholine in the brain, the use of drugs that inhibit this neurotransmitter seemed contradictory and threatening to us.

We kept asking ourselves: Were we then increasing the risk of a patient developing dementia by treating them with this class of drugs?

Although animal studies had already shown that acetylcholine inhibition promotes the formation of amyloid plaques and Tau-neurofibrillary tangles (specific pathological markers of Alzheimer’s disease) in regions linked to demencia, we did not have, by that time, any clinical study proving that anticholinergic drugs (i.e., acetylcholine inhibitors) could in fact cause cognitive deficits.

With the increasing incidence of Alzheimer’s disease and the ineffectiveness of currently available medications, studies addressing the risk factors for the development of this disease are becoming more and more important. These factors accelerate cognitive decline and, therefore, if avoided, have a “protective” effect, that is, they prevent the progression of memory loss and other characteristic changes of Alzheimer’s disease. We know that some of these factors cannot be modified, such as age or genetics. Others, however, are modifiable and their recognition allows preventing the appearance of new cases as well as the evolution of cases in early stages. Accordingly, it would be very important to find out whether anticholinergic drugs could be another risk factor.

A new study published in the journal Neurology (1), seems to provide an answer to my dilemma as a young neurologist:

In this study, 688 participants WITHOUT cognitive impairment were asked about the use of anticholinergic medications up to 3 months before the start of the study and followed up for 10 years. The authors found that the use of anticholinergic medications increased the risk of developing mild cognitive impairment (MCI) – an early stage of Alzheimer’s disease. This effect was dose dependent: the risk of MCI was higher in patients who used higher doses.

The interaction of anticholinergic use with the presence of the APOE4 genetic risk factor was also studied: patients carrying the APOE4 gene who used this type of drug were 2.5 times more likely to develop mild cognitive impairment than APOE4 negative patients who did not use the drug, showing an overlap of risk factors. The same association was observed for patients with specific markers for Alzheimer’s disease in cerebrospinal fluid.

We can conclude, therefore, that there is an association between the use of anticholinergic medications and the consequent progression to mild cognitive impairment within 10 years, accelerating memory loss and cognitive decline. This acceleration may be exacerbated in APOE4+ patients or in patients who have pathological markers for AD in their liquor (cephalo-spinal fluid CSF).

We must remember that anticholinergic medications are not only used in neurological clinics. Many commonly used drugs, sometimes used as self-medication, and sold without a prescription have this effect. Among them are antihistaminic (anti-allergic) medications, antiemetics (for motion sickness), muscle relaxants, antidepressants, antispasmodics, bronchodilators, etc. A detailed list of these medications can be found here on the KsD site.

These findings underscore the adverse impact of anticholinergic medications on cognition, particularly among individuals with elevated risk for AD. Physicians should carefully evaluate whether the benefit of using anticholinergic medications outweighs the risk of developing cognitive impairment. Patients should be warned about the risks and avoid self-medication. In addition, the current use of these medications should be evaluated in every patient diagnosed with mild cognitive impairment and discontinued whenever possible. Further studies should be done to evaluate whether discontinuation of such medications leads to improvement in cognition.

Conclusion:

Anticholinergic medications inhibit acetylcholine, a neurotransmitter involved in attention and memory. These drugs are commonly used to treat different symptoms such as asthma, Parkinson, pain, nausea, depression, etc. and can be bought in any drugstore without prescription. A new study showed that patients who use anticholinergic drugs have increased the risk of developing mild cognitive impairment (MCI), an early stage of Alzheimer’s disease. The risk is greater in APOE4 carriers. It is, therefore, extremely important to make a careful cost-benefit assessment when taking these drugs so that people do not expose themselves unnecessarily to a higher risk of dementia. Especially those who are already exposed to other risk factors should make this effort. Your brain health will thank you!

Reference:

Weigand AJ, Bondi MW, Thomas KR, Campbell NL, Galasko DR, Salmon DP, Sewell D, Brewer JB, Feldman HH, Delano-Wood L; Alzheimer’s Disease Neuroimaging Initiative. Association of anticholinergic medications and AD biomarkers with incidence of MCI among cognitively normal older adults. Neurology. 2020 Oct 20;95(16):e2295-e2304.