“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.”
–Alexandra Weigand, researcher
A study published this month in Neurology confirmed prior findings that a certain type of drug — anticholinergics — can be problematic, especially for older adults. Further, the new research found that for those who already had either the biomarkers or genetic risk factors of Alzheimer’s disease, that risk multiplies several times over.
There are approximately 100 anticholinergic drugs in widespread use. Some require a prescription. Others are available over the counter. They may treat allergies, colds, high blood pressure, motion sickness, urinary incontinence, or depression among other issues.
“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, PhD, associate professor in the Department of Psychiatry at UC San Diego School of Medicine, said in a statement.
“This is of course concerning and is a potential area for improvement that could possibly lead to a reduction in cases of mild cognitive impairment. It is also a possible target toward a future precision medicine approach because we can more carefully consider and prescribe medications for people depending upon their risk profile for neurodegenerative disorders like Alzheimer’s disease.”
The new study found that cognitively normal people taking at least one anticholinergic drug were 47% more likely to develop mild cognitive impairment, which can be a precursor to dementia, over the next decade than people who were not taking such drugs.
The study also determined that those with biomarkers for Alzheimer’s disease (the presence of beta-amyloid deposits or tau tangles in the brain) in their cerebrospinal fluid were four times more likely to later develop mild cognitive impairment — and those with genetic risk factors such as APOE4 gene were 2.5 times as likely — when taking anticholinergic drugs, than those without either Alzheimer’s link who did not take the drugs.
“We believe this interaction between anticholinergic drugs and Alzheimer’s risk biomarkers acts in a ‘double hit’ manner,” said lead author Weigand, a graduate student in the San Diego State University-University of California San Diego Joint Doctoral Program in Clinical Psychology. “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.”
Anticholinergic drugs block, or antagonize, the actions of a neurotransmitter called acetylcholine that is released by brain cells in order to signal the brain for functions like muscle contractions, learning and memory in the brain. Delano-Wood’s team monitored 688 cognitively healthy study participants, average age 74, for ten years, comparing the third of the group who self-reported use of anticholinergic drugs — most commonly, metoprolol, atenolol, loratadine and bupropion — with the other participants.
Different drugs have different levels of anticholinergic activity, so the team adjusted for participants’ overall anticholinergic burden based on the number, dosage, and strength of anticholinergic drugs they were taking. Of the 230 people who were taking anticholinergic drugs, approximately half – 51% – developed mild cognitive impairment (MCI) over the decade-long course of observation, compared to 42% who were not. Upon adjusting for depression, quantity of medications taken and history of cardiac problems, the researchers found that those who were taking at least one anticholinergic drug had a 47% increased risk for developing MCI. Higher exposure to anticholinergic drugs correlated to higher likelihood of developing MCI.
Because older people metabolize anticholinergic drugs differently than younger people, many anticholinergic drugs have different recommended daily dosages per age group. According to Delano-Wood, the majority of medications in the study were being taken at levels much higher than the lowest effective dose recommended for older adults, with 57% taken at twice the recommended dosage and 18% at least four times the recommended dosage.
According to the study authors, people taking anticholinergic medications should discuss medications with healthcare provider before making medication changes, as the sudden cessation of certain medications may cause adverse effects.
“Future studies are needed to see if indeed stopping the use of these drugs could lead to a reduction in mild cognitive impairment and Alzheimer’s disease down the road,” Delano-Wood said.