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Am J Geriatr Pharmacother. 2006 Sep;4(3):273-86.

Sex influences on cholinesterase inhibitor treatment in elderly individuals with Alzheimer's disease.

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Institute for Aging and Health, University of Newcastle, Newcastle, United Kingdom.



The second generation of cholinesterase inhibitors (ChEIs) is approved in the United Kingdom for the treatment of mild to moderate Alzheimer's disease (AD). The UK National Institute of Clinical Excellence has raised questions, however, about whether ChEIs are cost-effective for the treatment of dementia. To address these concerns, it is important to identify factors that predict which patients may have the best response to ChEl treatment.


We reviewed animal studies and human clinical studies to address whether sex can predict and influence the response to ChEI treatment based on differences in neuroanatomy, pharmacokinetics, and prevalence of dementia.


Relevant articles examining the use of ChEIs in humans with dementia (especially in AD) and in animals were identified through searches of several databases, including MEDLINE, PubMed, and EMBASE for general medical topics, the Cochrane Controlled Clinical Trials Register and CINAHL DIRECT for nursing and allied health issues, and PsycLIT for reviews of psychology and psychiatry topics (1980 June 2006). Articles reviewed were limited to those that discussed the use of ChEIs in relation to sex.


Animal studies have produced a substantial amount of evidence to support the hypothesis that sex may influence the response to ChEIs and, in particular, that testosterone may play a significant role in producing this difference by its influence on the entry of ChEIs into the brain. The results of clinical studies in humans, on the other hand, have been mixed. Two double-label and open-label clinical studies suggested that there may be a 3-way interaction between apolipoprotein E genotype, sex, and tacrine (range, P = 0.03 to P = 0.05). Seven double-blind, open-label clinical trials and 13 case studies of donepezil, rivastigmine, and galantamine produced little evidence of an association between treatment outcomes (as measured with clinical rating scales) and sex, although in an open-label 2-year study in women with AD treated with donepezil, women had lower mortality rates than men (10% and 20%, respectively; P = 0.003). One study produced weak evidence that women treated with ChEIs may experience more adverse effects than men, but this may have been attributable to low body weight rather than to sex differences.


A substantial relation has not been established between sex and the second-generation ChEIs currently used in clinical settings for the treatment of AD. If an interaction between sex and ChEI treatment does exist, as suggested in 10 of the studies we analyzed, it is likely to be small and subtle, with much individual variation, as is the case with most neurologic sex differences. Nevertheless, sexual dimorphism in response to ChEI therapy warrants further investigation, especially in regard to its role in the development of novel AD therapies.

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