Literature Review

Long-Term Benzodiazepine Use May Increase Risk of Alzheimer’s Disease



Benzodiazepine use for three months or more is associated with a significantly increased likelihood of developing Alzheimer’s disease, and longer exposure is associated with greater likelihood, according to results from a case–control study published September 9 in BMJ.

Sophie Billioti de Gage, a doctoral candidate at the Université de Bordeaux in France, and colleagues conducted a nested case–control study of 1,796 members of a public drug plan in Québec, Canada, who were age 66 or older and had been diagnosed with Alzheimer’s disease at least six years before. The study also included more than 7,000 controls without Alzheimer’s disease, matched for age and sex.

The investigators found a cumulative dose–effect association between exposure to benzodiazepines at least five years before diagnosis and the odds of developing Alzheimer’s disease. The researchers observed a significantly greater likelihood of developing Alzheimer’s disease with benzodiazepine use of 90 or more consecutive days (adjusted odds ratio, 1.51) and with daily exposure to benzodiazepines for 180 or more days (adjusted OR, 1.84).

The researchers also found that the type of benzodiazepine prescribed affected the risk. Drugs with longer half-lives, such as diazepam and clonazepam, were associated with a greater likelihood of developing Alzheimer’s disease (OR, 1.70), compared with shorter-acting drugs, such as lorazepam and alprazolam (OR, 1.43). The association between benzodiazepine use and Alzheimer’s disease persisted after the investigators adjusted for symptoms that could indicate a future dementia diagnosis, including depression, anxiety, and insomnia.

Although the study authors noted that they could not rule out that anxiety and sleep disorders, two of the main indications for benzodiazepines, “could be associated with early beta-amyloid lesions in [the] brain, and persistent midlife anxiety could be associated with a greater risk of dementia in older people,” they also noted that their study was designed to reduce the possibility of reverse causation bias “and to provide additional arguments linking benzodiazepine use with Alzheimer’s disease, such as a dose–effect relation.” The findings underscore the necessity of “carefully evaluating the indications for use of this drug class ... especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries,” said Ms. Billioti de Gage.

Jennie Smith

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