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Benzos, Related Z-drugs Associated With Increased Risk of Alzheimer Disease

A nationwide, case-controlled study found the use of benzodiazepines and related z-drugs increased the risk of patients developing Alzheimer disease.

The use of benzodiazepines and related z-drugs (BZDRs) was found to be associated with a modest increase in the risk of Alzheimer disease in a case-control trial.1

Findings revealed an adjusted odds ratio (OR) of 1.06 (95% CI, 1.04 to 1.08) of a patient developing Alzheimer after exposure to benzodiazepines. Additionally, a dose-response relationship was observed with both cumulative consumption and duration, but that relationship was removed by adjustment for other psychotropics.

In the nationwide, nested study of all Finnish community-dwelling people with a clinically verifiable Alzheimer diagnosis (n = 70,719) from 2005 to 2011 and a matched control group (n = 282,862), a research team led by Vesa Tapiainen, MD, from the School of Pharmacy at the University of Eastern Finland, in Kuopio, assessed the association between Alzheimer and the use of these sedative therapies. The average time for exposure assessment was 8.7 years (standard deviation [SD], 2.0), ranging from 5 years to 11.9 years.

“Even though the association between BZDR use and Alzheimer's disease was small in this study, BZDRs should be avoided when possible and [the] threshold for prescribing should be high enough due to their overall adverse effect profile,” Tapiainen and colleagues noted.

The team found that the use of any BZDRs was more common in the case group (40.2%) than the control group (37.0%), due to a more common use of BZDRs. The case group was also more likely to have used both benzodiazepines (21.4% vs. 20%) and z-drugs (7.6% vs. 7.3%), or short-, medium-, and long-acting BZDRs (12.6% vs. 10.9%).

Any use of BZDRs was associated with an increased risk of Alzheimer (OR, 1.19; 95% CI, 1.17 to 1.21) compared with no use, though that association was lessened after adjusting for socioeconomic position, comorbidities, and the use of other psychotropics. “The attributable proportion among the exposed was 0.057. Similar associations were observed with the use of BZD or Z drug alone. The same pattern was observed with short‐/medium‐ and long‐acting BZDRs,” Tapiainen and colleagues noted.

The average dose analysis revealed that unadjusted ORs were slightly higher in those with a lower average dose of BZDRs compared to those with higher doses. The low-dose BZDR cohort (>0 to <0.5 DDD/day) had an unadjusted OR of 1.22 (95% CI, 1.19 to 1.26), compared to 1.16 (95% CI, 1.13 to 1.19) with the higher dose cohort (≥1 DDD/day). The same finding was shown in those using just benzodiazepines, though it was not evident among those using just z-drugs in the low-dose group. The differences overall were small, and the confidence intervals tended to overlap, with adjustments removing the associations in the higher-dose groups without altering the risk order.

Tapiainen and colleagues noted that “assuming there was no uncontrolled bias or confounding, 5.7% of AD cases occurring among BZDR users were attributable to exposure. This is worrying because BZDRs are commonly used among old persons, and despite recommendations, the use is often long-term.”

Adding to that trouble is the recent finding that z-drugs increase the risk of falls for elderly patients with dementia, who themselves are already at an increased risk for falls.2 At the Alzheimer Association International Conference in Chicago, Illinois, Ian Maidment, PhD, a senior lecturer in Clinical Pharmacy at Aston University, told NeurologyLive that the neurology community moved away from benzodiazepines to z-drugs due to the belief that the z-drugs were safer. “We don't probably don't think they are safer now,” he said.

“I think the thing is if you give someone a sedative to help them sleep, you're probably going to increase the risk of fall at some stage, and probably the biggest risk is not when they first take it, but in the morning, when you get a hangover effect,” Maidment said. “They feel quite groggy, so probably most sedatives would cause [those effects]. People have looked at melatonin and that is sometimes used, but I'm not sure how strong the evidence is for that. I think the key focus, for sleep problems in older people, should be non-medication [interventions].”


1. Tapiainen V, Taipale H, Tanskanen A, et al. The risk of Alzheimer's disease associated with benzodiazepines and related drugs: a nested case—control study. Acta Psychiat Scand. doi: 10.1111/acps.12909.

2. Fox C, Richardson K, Loke Y, et al. The Z-drugs in Dementia (ZED) study. Presented at: 2018 Alzheimer Association International Conference; July 25, 2018; Chicago, IL. Accessed August 17, 2018.