Benzodiazepine Use and Risk of Alzheimer's Disease
This case-control study based on 8980 individuals representative of elderly people living in the community in Quebec showed that the risk of Alzheimer’s disease was increased by 43-51% among those who had used benzodiazepines in the past. Risk increased with density of exposure and when long acting benzodiazepines were used. Further adjustment on symptoms thought to be potential prodromes for dementia—such as depression, anxiety, or sleep disorders—did not meaningfully alter the results.
Our findings are congruent with those of five previous studies, two of which explored the modifying effect of the dose used. In four studies, the role of a putative protopathic bias could not be ruled out because an insufficient duration of follow-up; a lack of statistical power in subgroup analyses; and no consideration of the most relevant time window for exposure and ascertainment of confounders. The most recent study found a similar 50% increased risk within the 15 years after the start of benzodiazepine use (average length of follow-up 6.2 years). This excess risk was delayed and thus not indicative of a reverse causality bias. Another study found a positive association, though lacked significance because of its limited sample size. The earliest work observed a paradoxical protective effect of benzodiazepines, which could be partly explained by the misclassification of past users as a part of the reference group.
Our study was designed specifically 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.
Firstly, we assessed benzodiazepine treatments initiated more than five years (six years in the sensitivity analysis) before the diagnosis of Alzheimer’s disease, a period when prescriptions were less likely to be motivated by the prodromes of the disease. This allowed better control for reverse causation bias, as did further adjustment on anxiety, depression, and insomnia, which did not alter the strength or the significance of the association.
A second added value of our study was the exploration of a possible dose-effect relation, a criterion necessary to establish robust links between benzodiazepine use and risk of Alzheimer’s disease. The risk associated with the lowest cumulative levels of exposure (<90 prescribed daily doses (PDDs)) did not differ from that seen in controls, while the risk was increased by 32% and 84% for 91-180 PDDs and >180 PDDs, respectively. The higher odds ratio associated with long acting benzodiazepines (half life ≥20 hours) also argues in favour of a dose-response effect. Indeed, unlike products with short half lives, these molecules used daily result in more or less constant blood and brain active concentrations.
Finally, our study population was representative of older people of Quebec, which makes the findings generalisable.
The limitations of the study are shared with other studies that use claims databases without direct access to patients. As case ascertainment was based on diagnoses recorded in claims data, misclassification was possible, even if diagnoses were always made by a physician (general practitioner, neurologist, internist, or geriatrician). Similarly, there could have been a delay between the actual date of onset of Alzheimer’s disease and the date of its recording (index date for our study).
In the Quebec public drug plan, treatments with cholinesterase inhibitors are reimbursed only for patients having a mini-mental state examination score ranging between 10 and 26 at initiation. Furthermore, maintenance of reimbursement after a course of treatment of six months requires both an absence of notable worsening and an improvement in at least one cognitive function. These criteria, fulfilled in 72% of patients with Alzheimer’s disease in this study, clearly imply the repeated use of validated diagnostic tools. For this reason, diagnostic misclassification was unlikely to be a major concern. Moreover, misclassification of some unaffected people as cases and some cases as controls would reduce the exposure difference between the groups, making the estimates more conservative.
In regard to a possible delay in recording a diagnosis of Alzheimer’s disease, one should note that pushing back the index date by one year in the sensitivity analysis did not alter the results.
It could also be argued that benzodiazepine use might confound the clinical diagnosis of dementia by impairing cognitive functions. This seems unlikely as odds ratios in those who used benzodiazepines for more than six months were 1.72 (95% confidence interval 1.51 to 1.97) and 2.51 (1.97 to 3.20) for treatments still underway at the date of diagnosis or discontinued for at least one year before, respectively.
We compared exposure on the basis of information recorded in the database without the possibility of ascertaining whether the dates of benzodiazepine claims corresponded to their actual consumption. Nevertheless, the excess risk found in our study concerned only long term treatments that required multiple refilled prescriptions, which does not support non-compliance. Therefore, observed long lasting uses were likely to correspond to actual exposures.
Neuropsychiatric symptoms used for adjustment—such as anxiety, depression, and sleep disorders—could have been under-reported if they were not considered by the physician as a main diagnosis. This limitation, which is common to other databases widely used in pharmacoepidemiology, could be deleterious only if it is notable and not balanced across the groups. Moreover, in our study sample, anxiety was recorded in 21.4% of cases and 15.1% of controls; for depression, percentages were 2.9% and 2.4%, respectively. These figures do not seem to depart markedly from prevalences found in the literature for people aged >65.
The RAMQ database does not contain information on socioeconomic status, education level, smoking habits, or alcohol consumption. Smoking and alcohol consumption are known to be associated with benzodiazepine use but not a priori with Alzheimer type dementia, even if chronic wine consumption has been claimed to be a protective factor. The effect of not adjusting for these factors was likely to be conservative as benzodiazepine use is thought to be higher in regular wine and alcohol consumers. Socioeconomic and educational levels have been shown to be inversely correlated with the risk of presenting with dementia, and thus lack of adjustment for these factors could results in bias. Their association with benzodiazepine use, however, remains unclear as it has been reported as absent, positive, or negative.
Finally, we cannot rule out alternative hypotheses. For example, anxiety and sleep disorders, two of the main indications for benzodiazepines, could be associated with early Β amyloid lesions in brain, and persistent mid-life anxiety could be associated with a greater risk of dementia in older people. Therefore, benzodiazepine use might be an early marker of a condition associated with an increased risk of dementia and not the cause.
The deleterious effects of benzodiazepines on memory are well documented. No univocal pathophysiological mechanism, however, can be reasonably advanced to explain an increased risk of dementia. Recently, a systematic review underlined that benzodiazepine use induces both non-amnestic and amnestic mild cognitive impairment; a faster progression of Alzheimer’s disease being observed in the latter form. Chronic administration of benzodiazepines also induces a down-regulation of their binding receptors, and a reduction in the number of these receptors seems to be correlated with cognitive decline.
Under a causal assumption, the most plausible hypothesis would be the limitation in cognitive reserve capacity induced by the long term use of benzodiazepines, which might reduce a person’s ability to cope with early phase brain lesions by soliciting accessory neuronal networks. A unique approach to further investigation of causality would be, if feasible, to turn to experimental animal models in an attempt to identify a possible biological mechanism.
Benzodiazepines are indisputably valuable tools for managing anxiety disorders and transient insomnia. As stated in international guidelines, however, treatments should be of short duration and not exceed three months.
Our study reinforces the suspicion of an increased risk of Alzheimer type dementia among benzodiazepine users, particularly long term users, and provides arguments for carefully evaluating the indications for use of this drug class. Our findings are of major importance for public health, especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries. In such conditions, a risk increased by 43-51% in users would generate a huge number of excess cases, even in countries where the prevalence of use of these drugs is not high.
To date, no preventive or curative treatment has been shown to be satisfactorily effective in Alzheimer’s disease. For this reason, the search for putative alterable risk factors should be prioritised. Long term use of benzodiazepines and related drugs (such as other anxiolytics and hypnotics) could be a candidate because their association with Alzheimer’s disease is at least plausible and this factor is typically alterable as only use over three months (that is, outside international recommendations and without a priori therapeutic justification) seems to be associated with an excess risk. This putative impact, added to other adverse consequences such as fractures related to falls, should be seriously considered by regulatory agencies and prescribers. In view of the evidence, it is now crucial to encourage physicians to carefully balance the benefits and risks when initiating or renewing a treatment with benzodiazepines and related products in older patients. Despite the lack of data in younger adults, the precautionary principle would also support extending that recommendation to them.
Experimental animal or cellular models are needed to help in identifying a possible biological mechanism linking benzodiazepines with risk of Alzheimer’s disease. Studies based on a long follow-up—that is, at least 20-30 years—would make it possible to evaluate the risk of long term use of benzodiazepines in younger adults and to better assess the exact role of anxiety, sleep disorders, and depression as putative early risk factors of future dementia.
Discussion
This case-control study based on 8980 individuals representative of elderly people living in the community in Quebec showed that the risk of Alzheimer’s disease was increased by 43-51% among those who had used benzodiazepines in the past. Risk increased with density of exposure and when long acting benzodiazepines were used. Further adjustment on symptoms thought to be potential prodromes for dementia—such as depression, anxiety, or sleep disorders—did not meaningfully alter the results.
Comparison With Other Studies
Our findings are congruent with those of five previous studies, two of which explored the modifying effect of the dose used. In four studies, the role of a putative protopathic bias could not be ruled out because an insufficient duration of follow-up; a lack of statistical power in subgroup analyses; and no consideration of the most relevant time window for exposure and ascertainment of confounders. The most recent study found a similar 50% increased risk within the 15 years after the start of benzodiazepine use (average length of follow-up 6.2 years). This excess risk was delayed and thus not indicative of a reverse causality bias. Another study found a positive association, though lacked significance because of its limited sample size. The earliest work observed a paradoxical protective effect of benzodiazepines, which could be partly explained by the misclassification of past users as a part of the reference group.
Strengths and Limitations
Our study was designed specifically 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.
Firstly, we assessed benzodiazepine treatments initiated more than five years (six years in the sensitivity analysis) before the diagnosis of Alzheimer’s disease, a period when prescriptions were less likely to be motivated by the prodromes of the disease. This allowed better control for reverse causation bias, as did further adjustment on anxiety, depression, and insomnia, which did not alter the strength or the significance of the association.
A second added value of our study was the exploration of a possible dose-effect relation, a criterion necessary to establish robust links between benzodiazepine use and risk of Alzheimer’s disease. The risk associated with the lowest cumulative levels of exposure (<90 prescribed daily doses (PDDs)) did not differ from that seen in controls, while the risk was increased by 32% and 84% for 91-180 PDDs and >180 PDDs, respectively. The higher odds ratio associated with long acting benzodiazepines (half life ≥20 hours) also argues in favour of a dose-response effect. Indeed, unlike products with short half lives, these molecules used daily result in more or less constant blood and brain active concentrations.
Finally, our study population was representative of older people of Quebec, which makes the findings generalisable.
The limitations of the study are shared with other studies that use claims databases without direct access to patients. As case ascertainment was based on diagnoses recorded in claims data, misclassification was possible, even if diagnoses were always made by a physician (general practitioner, neurologist, internist, or geriatrician). Similarly, there could have been a delay between the actual date of onset of Alzheimer’s disease and the date of its recording (index date for our study).
In the Quebec public drug plan, treatments with cholinesterase inhibitors are reimbursed only for patients having a mini-mental state examination score ranging between 10 and 26 at initiation. Furthermore, maintenance of reimbursement after a course of treatment of six months requires both an absence of notable worsening and an improvement in at least one cognitive function. These criteria, fulfilled in 72% of patients with Alzheimer’s disease in this study, clearly imply the repeated use of validated diagnostic tools. For this reason, diagnostic misclassification was unlikely to be a major concern. Moreover, misclassification of some unaffected people as cases and some cases as controls would reduce the exposure difference between the groups, making the estimates more conservative.
In regard to a possible delay in recording a diagnosis of Alzheimer’s disease, one should note that pushing back the index date by one year in the sensitivity analysis did not alter the results.
It could also be argued that benzodiazepine use might confound the clinical diagnosis of dementia by impairing cognitive functions. This seems unlikely as odds ratios in those who used benzodiazepines for more than six months were 1.72 (95% confidence interval 1.51 to 1.97) and 2.51 (1.97 to 3.20) for treatments still underway at the date of diagnosis or discontinued for at least one year before, respectively.
We compared exposure on the basis of information recorded in the database without the possibility of ascertaining whether the dates of benzodiazepine claims corresponded to their actual consumption. Nevertheless, the excess risk found in our study concerned only long term treatments that required multiple refilled prescriptions, which does not support non-compliance. Therefore, observed long lasting uses were likely to correspond to actual exposures.
Neuropsychiatric symptoms used for adjustment—such as anxiety, depression, and sleep disorders—could have been under-reported if they were not considered by the physician as a main diagnosis. This limitation, which is common to other databases widely used in pharmacoepidemiology, could be deleterious only if it is notable and not balanced across the groups. Moreover, in our study sample, anxiety was recorded in 21.4% of cases and 15.1% of controls; for depression, percentages were 2.9% and 2.4%, respectively. These figures do not seem to depart markedly from prevalences found in the literature for people aged >65.
The RAMQ database does not contain information on socioeconomic status, education level, smoking habits, or alcohol consumption. Smoking and alcohol consumption are known to be associated with benzodiazepine use but not a priori with Alzheimer type dementia, even if chronic wine consumption has been claimed to be a protective factor. The effect of not adjusting for these factors was likely to be conservative as benzodiazepine use is thought to be higher in regular wine and alcohol consumers. Socioeconomic and educational levels have been shown to be inversely correlated with the risk of presenting with dementia, and thus lack of adjustment for these factors could results in bias. Their association with benzodiazepine use, however, remains unclear as it has been reported as absent, positive, or negative.
Finally, we cannot rule out alternative hypotheses. For example, anxiety and sleep disorders, two of the main indications for benzodiazepines, could be associated with early Β amyloid lesions in brain, and persistent mid-life anxiety could be associated with a greater risk of dementia in older people. Therefore, benzodiazepine use might be an early marker of a condition associated with an increased risk of dementia and not the cause.
Biological Plausibility
The deleterious effects of benzodiazepines on memory are well documented. No univocal pathophysiological mechanism, however, can be reasonably advanced to explain an increased risk of dementia. Recently, a systematic review underlined that benzodiazepine use induces both non-amnestic and amnestic mild cognitive impairment; a faster progression of Alzheimer’s disease being observed in the latter form. Chronic administration of benzodiazepines also induces a down-regulation of their binding receptors, and a reduction in the number of these receptors seems to be correlated with cognitive decline.
Under a causal assumption, the most plausible hypothesis would be the limitation in cognitive reserve capacity induced by the long term use of benzodiazepines, which might reduce a person’s ability to cope with early phase brain lesions by soliciting accessory neuronal networks. A unique approach to further investigation of causality would be, if feasible, to turn to experimental animal models in an attempt to identify a possible biological mechanism.
Implications for Clinical Practice and Public Health
Benzodiazepines are indisputably valuable tools for managing anxiety disorders and transient insomnia. As stated in international guidelines, however, treatments should be of short duration and not exceed three months.
Our study reinforces the suspicion of an increased risk of Alzheimer type dementia among benzodiazepine users, particularly long term users, and provides arguments for carefully evaluating the indications for use of this drug class. Our findings are of major importance for public health, especially considering the prevalence and chronicity of benzodiazepine use in older people and the high and increasing incidence of dementia in developed countries. In such conditions, a risk increased by 43-51% in users would generate a huge number of excess cases, even in countries where the prevalence of use of these drugs is not high.
To date, no preventive or curative treatment has been shown to be satisfactorily effective in Alzheimer’s disease. For this reason, the search for putative alterable risk factors should be prioritised. Long term use of benzodiazepines and related drugs (such as other anxiolytics and hypnotics) could be a candidate because their association with Alzheimer’s disease is at least plausible and this factor is typically alterable as only use over three months (that is, outside international recommendations and without a priori therapeutic justification) seems to be associated with an excess risk. This putative impact, added to other adverse consequences such as fractures related to falls, should be seriously considered by regulatory agencies and prescribers. In view of the evidence, it is now crucial to encourage physicians to carefully balance the benefits and risks when initiating or renewing a treatment with benzodiazepines and related products in older patients. Despite the lack of data in younger adults, the precautionary principle would also support extending that recommendation to them.
Unanswered Questions and Future Research
Experimental animal or cellular models are needed to help in identifying a possible biological mechanism linking benzodiazepines with risk of Alzheimer’s disease. Studies based on a long follow-up—that is, at least 20-30 years—would make it possible to evaluate the risk of long term use of benzodiazepines in younger adults and to better assess the exact role of anxiety, sleep disorders, and depression as putative early risk factors of future dementia.
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