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Previous research has found an inconsistent relationship with dementia and benzodiazepines – a group of sedative drugs used to treat conditions such as anxiety and insomnia. Now, using the DPUK Data Portal, a team of researchers in France has investigated the association further and found compelling evidence that benzodiazepines reduce some of the hallmarks of Alzheimer’s disease.

A woman's hand filled with round white pills.

The difficulty with studying how benzodiazepines (BZDs) affect dementia is that the conditions they are prescribed for may also influence dementia risk. To gain a more accurate picture of the association, the latest research paper on the subject – published in the journal Neuropsychopharmacology and conducted by the MEMENTO study group – tightly controlled for these confounding variables.

Dr Thomas Desmidt, a member of the MEMENTO study group, said: ‘We wanted to bring pathophysiological arguments to the debate about the links between Alzheimer’s disease and benzodiazepines, which are widely prescribed drugs in older adults. We had previously found that the chronic use of benzodiazepines in cognitively healthy older adults was associated with lower amyloid load in the brain. Here, we not only replicated these results but also extended the association to another marker related to Alzheimer’s disease, the volume of the hippocampus brain region, in a large cohort of older adults.’

Alzheimer’s disease is often associated with a high amyloid load, which means people have lots of a protein called amyloid in their brains. You can find out more about amyloid and other proteins linked to dementia in this blog post. People with Alzheimer’s disease may also have a smaller hippocampus, a part of the brain responsible for memory – you can read more about different brain areas in this blog post.

Existing research has suggested that people who take BZDs have a lower amyloid load, but research relating to the size of their hippocampi is unclear. The MEMENTO study group (composed of clinicians and experts in neuroimaging) aimed to confirm the previous findings about amyloid load and identify whether hippocampal volume varied between those taking BZDs and those not.

They conducted their research in the DPUK Data Portal, using 2,323 people from the MEMENTO cohort, a large group of French people with some memory issues but not dementia who did various tests over five years, including brain scans. A type of scan called a PET scan revealed how much amyloid they had in their brains, while a different brain scan called an MRI showed their hippocampal volume. 

The researchers found that people taking BZDs had a lower amyloid load and a higher hippocampal volume than those not taking BZDs. They identified even larger hippocampi in people taking short-acting BZDs as opposed to BZDs that work over a longer period. However, the researchers saw no effect of dose and duration of BZD use, which is consistent with previous research.

BZDs increase the ability of the chemical messenger GABA to bind to its receptor on certain brain cells called GABAergic neurones. When GABA binds, it decreases the activity of these neurones. Interestingly, neuronal hyperactivity has been linked to amyloid formation, damage to neurones and, ultimately, dementia.

Plus, there is evidence that toxic amyloid proteins could be involved in the shrinkage of the hippocampus, meaning the larger hippocampal volumes seen in people taking BZDs could be due to their lower amyloid burden. The short-acting BZDs bind to GABA receptors that are more abundant in the hippocampus, which could explain why this type of drug was linked to a more significant increase in hippocampal volume.

Therefore, these results support the theory that the GABA system could be targeted to help prevent the biological mechanisms that can lead to dementia. However, the authors warn that they have only identified an association and that future long-term studies are needed to confirm whether BZDs have a causal effect on hippocampal volume and amyloid load.

Dr Desmidt added: ‘Our findings suggest there may be mechanisms related to the pharmacological effects of benzodiazepines that may limit Alzheimer’s disease brain pathology. Nevertheless, benzodiazepines have potentially several side effects and certainly may not be prescribed for more than a few weeks.’

Negative side effects of BZDs include increased risk of falls, drug dependence, and cognitive impairment, which ultimately outweigh the potential benefits against dementia. Instead, the authors propose GABAergic neurones as a potential therapeutic target for preventing dementia and call for more research in this area.