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Neuropathological Correlates of Cumulative Benzodiazepine and Anticholinergic Drug Use.

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Richardson, Kathryn 
Wharton, Stephen B 
Grossi, Carlota M 
Matthews, Fiona E 
Fox, Chris 


BACKGROUND: Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited. OBJECTIVE: To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs. METHODS: We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders. RESULTS: Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer's disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95% CI] 0.18-0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11-19.24) and 3.30 (1.02-10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders. CONCLUSIONS: We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer's disease; however, we cannot rule out effects owing to small numbers.



Alzheimer’s disease, basal nucleus of Meynert, benzodiazepines, cholinergic antagonists, neuritic plaques, neurofibrillary tangles, neuropathology, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Atrophy, Basal Nucleus of Meynert, Benzodiazepines, Cerebral Cortex, Cholinergic Antagonists, Cognition, Cost of Illness, Dementia, Female, Humans, Male, Neurofibrillary Tangles, Substantia Nigra

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J Alzheimers Dis

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IOS Press


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Medical Research Council (G0601022)
Medical Research Council (G9901400)
Medical Research Council (MR/J004308/1)
Medical Research Council (G0300126)
Medical Research Council (G0900582)
Medical Research Council (G0601022/1)
Medical Research Council (G0900582/1)
This research was supported by funding from the Alzheimer’s Society (AS-PG-2013-017). Work in the individual CFAS centres is supported by the UK NIHR Biomedical Research Centre for Ageing and Age – awarded to Newcastle-upon-Tyne Hospitals Foundation Trust; Cambridge Brain Bank supported by the NIHR Cambridge Biomedical Research Centre; Nottingham University Hospitals NHS Trust; University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield NIHR Biomedical Research Centre; The Thomas Willis Oxford Brain Collection, supported by the Oxford Biomedical Research Centre; The Walton Centre NHS Foundation Trust,  Liverpool. We would like to acknowledge the essential contribution of the liaison officers, the general practitioners, their staff, and nursing and residential home staff. We are grateful to our respondents and their families for their generous gift to medical research, which has made this study possible.