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. 2020 Jan 8;11:344.
doi: 10.3389/fnagi.2019.00344. eCollection 2019.

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

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Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia

Miren Ettcheto et al. Front Aging Neurosci. .
Free PMC article


Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990-2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile.

Keywords: Alzheimer's disease; benzodiazepines; cognition; dementia; risk factors.


Figure 1
Figure 1
Schematic representation of potential pathways by which insomnia and benzodiazepines could increase AD risk. Insomnia is a CNS stressor, which induces microglial activation and oxidative stress. Likewise, oxidative stress may be involved in cognitive impairment by decreasing phosphorylation levels of p-CREB and altering dendritic spines and synapses. Moreover, sleep disturbances prevent clearing toxic metabolites such as β-amyloid. These lead to an increased production of inflammatory cytokines and the formation of Aβ-plaques. In turn, BZDs activate GABAA receptors, thus interfering excitatory synapses and decreasing cognitive reserve. Moreover, these drugs have been shown to decrease BDNF as well as increase β-amyloid precursor protein (APP) mRNA levels and tau phosphorylation. All these mechanisms could increase the risk of cognitive impairment through neuroinflammation, decrease synaptic plasticity and brain insulin signaling as well as accumulation of Aβ plaques and neurofibrillary tangles.

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