Researchers have identified a mechanism that could explain the association between anticholinergic drugs and the risk of dementia.
In a mouse model, the team, led by Marco Prado from Western University in London, Ontario, showed that blocking acetylcholine (Ach) – the effect of anticholinergic drugs – affects the regulation of messenger RNA (mRNA) transcription in areas of the brain involved in memory and leads to changes similar to those observed in Alzheimer’s disease.
In Cerebral Cortex
(online, 16 June 2016), the researchers say their findings shed light on the role of cholinergic dysfunction in the development of the disease. “We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer’s pathology,” Prado says.
The team used genetically modified mice with a deletion of a transporter in the forebrain, which is required for ACh release. The mice were designed as a model for early Alzheimer’s disease, during which time a marked decrease in cholinergic neurons in the basal forebrain accompanies cognitive decline.
The researchers found that this cholinergic deprivation altered the production of certain mRNA transcripts related to Alzheimer’s disease in the hippocampus, a major area involved in memory and spatial navigation.
In particular, it resulted in abnormal mRNA splicing of BACE1, a gene that encodes an enzyme involved in cleaving amyloid precursor protein (APP). The subsequent increase in BACE1 production resulted in upregulated APP processing, leading to a ten-fold increase in soluble amyloid-beta proteins – a hallmark of Alzheimer’s disease – in the hippocampi.
Other changes include decreased levels of synaptic markers, increased neuronal death and cognitive decline, as well as several other age-related pathologies, when compared with normal mice.
“We demonstrated that in order to keep neurons healthy, you need acetylcholine,” says Prado. “So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer’s disease.”
James Pickett, head of research at UK charity Alzheimer’s Society, says that research like this, which looks at the causes of damage in the brain, can lead to a better understanding of the early changes that may lead to dementia.
“Although this study in mice didn’t look directly at the effects of these drugs, it shows that decreasing the amount of acetylcholine in the brain can trigger processes that may lead to brain cell damage,” he says.
In 2015, a study by researchers at the University of Washington found that anticholinergic exposure in older adults was associated with a dose-dependent increase in the risk of dementia, over ten years.
However, Pickett says that it is still unclear whether this association is related only to continuous use or also to occasional use of the drugs, which are used to treat allergies, depression and bladder complaints.
“More research into the potential link between anticholinergic use and dementia risk is certainly warranted, but we can’t yet say what this means for people who only take them occasionally for conditions such as hayfever. We need to understand more about the possible effects, and we encourage doctors and pharmacists to be aware of this potential link.”