Benzodiazepine use for 3 months or more is associated with a significantly increased likelihood of developing Alzheimer’s disease, and longer exposure is associated with greater odds, according to results from a case-control study published Sept. 9 in BMJ.
The authors, led by Sophie Billioti de Gage of Université de Bordeaux (France), conducted a nested case-control study of 1,796 members of a public drug plan in Quebec, Canada, aged 66 years and older who had been diagnosed with Alzheimer’s disease at least 6 years prior, and more than 7,000 non-Alzheimer’s controls matched for age and sex.
Ms. Billioti de Gage and her colleagues found a cumulative dose-effect association between exposure to benzodiazepines at least 5 years before diagnosis and the odds of developing Alzheimer’s disease, with a significantly greater likelihood observed with benzodiazepine use of 90 or more consecutive days (adjusted odds ratio, 1.51; 95% confidence interval, 1.36-1.69) and daily exposure to benzodiazepines for 180 or more days (adjusted OR, 1.84; 95% CI, 1.62-2.08).
The researchers also found that the type of benzodiazepine prescribed affected risk. Drugs with longer half-life, such as diazepam and clonazepam, were associated with greater likelihood of Alzheimer’s disease (OR, 1.70; 95% CI, 1.46-1.98), compared with shorter-acting drugs, such as lorazepam and alprazolam (OR, 1.43; 95% CI, 1.27-1.61). The association between benzodiazepine use and Alzheimer’s persisted even after researchers adjusted for symptoms that could be indicative of a future dementia diagnosis, including depression, anxiety, and insomnia (BMJ 2014 Sept. 9 [doi:10.1136/bmj.g5205]).
While the study authors acknowledged 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 brain, and persistent mid-life 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, Ms. Billioti de Gage and her colleagues added, argue for "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."
The study was funded by INSERM (Institut National de la Santé et de la Recherche Médicale) and the University of Bordeaux, as well as by unconditional grants from IRESP (Institut de Recherche en Santé Publique), the French Ministry of Health (Direction Générale de la Santé), and the Funding Agency for Health Research of Quebec (Fonds de la Recherche en Santé du Québec). One of the study’s coauthors, Dr. Tobias Kurth, declared payment from BMJ and Cephalalgia; another co-author, Marie Tournier, declared receiving honoraria from AstraZeneca, Bristol-Myers Squibb, and Janssen.