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Drug repositioning for Alzheimer's disease

Abstract

Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.

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Acknowledgements

The authors thank: the UK Alzheimer's Society for supporting this work; I. Testad and E. Perry for their contributions to the consensus process; and the UK National Institute for Health Research (NIHR) Biomedical Research Unit at South London and Maudsley UK National Health Service (NHS) Trust/King's College London for supporting the involvement of C.B. in this work.

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Correspondence to Clive Ballard.

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Clive Holmes is in receipt of a grant from Pfizer to investigate peripherally administered etanercept. The UK Alzheimer's Society supported Anne Corbett, James Pickett, Emma Jones, Ian Kearns and Clive Ballard in the preparation of this manuscript. The other authors declare no competing financial interests.

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Glossary

APP23 mice

Transgenic mice carrying the double Swedish mutation (K670N/M671L) of amyloid precursor protein (APP), which leads to familial Alzheimer's disease. These animals overexpress APP by about sevenfold and develop amyloid deposits and behavioural deficits as they age.

APP/PSEN1 mice

A transgenic mouse model of Alzheimer's disease carrying both human amyloid precursor protein (APP) with the Swedish mutation (K670N/M671L) and the presenilin 1 (PSEN1) A246E mutation. These mice develop amyloid deposits and behavioural deficits at a younger age than the APP transgenic animals (K670N/M671L models alone).

Delphi-type process

A structured technique to achieve consensus from a panel of experts using a systematic method, usually using two or more stages to share and discuss the emerging consensus in order to achieve the best overall consensus from the expert group.

J20 mice

A transgenic mouse model of Alzheimer's disease. These mice express a mutant form of human amyloid precursor protein (APP) bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations of familial Alzheimer's disease. These mice develop amyloid deposits and behavioural deficits as they age.

Mini mental state examination

(MMSE). A brief and widely used 30-point neuropsychological assessment evaluating a number of cognitive domains. A score of 25 or less is indicative of a degree of cognitive deficit requiring further evaluation. In patients with Alzheimer's disease, an MMSE score <10 indicates severe dementia, 10–20 indicates moderate dementia and >20 indicates mild dementia.

Non-APOE4 carriers

Individuals who do not carry the E4 allele of the gene encoding apolipoprotein E (APOE); APOE4 is a known risk factor for the development of late-onset Alzheimer's disease; 25% of the population and 50% of patients with Alzheimer's disease carry at least one E4 allele.

'Peripheral sink' hypothesis

A hypothesis stating that antibodies bind to amyloid-β in the bloodstream, shifting the distribution of amyloid-β between the brain and the peripheral circulatory system and thereby leading to a net efflux of amyloid-β from the central nervous system to plasma, where it is degraded.

Standardized mean difference

(SMD). A statistical method for calculating a standardizing coefficient to quantify differences between treatment groups based on mean changes and standard deviation to enable comparison of outcomes across studies that have used different outcome measures.

Tg2576 transgenic mice

Transgenic mice expressing abnormal variants of the human genes encoding amyloid precursor protein (APP) that are a rare cause of familial Alzheimer's disease. These mice exhibit a fivefold increase in APP levels in the brain and develop amyloid deposits and behavioural deficits as they age.

Triple-transgenic mice

(3xTg-AD mice). A novel mouse model of Alzheimer's disease, incorporating human genes that lead to abnormal processing of amyloid-β and tau. This mouse model is the only model to exhibit both amyloid-β and tau pathology, and therefore mimics human Alzheimer's disease more closely than other mouse models.

Weighted mean difference

(WMD). A statistical method for calculating a standardizing coefficient to quantify differences between treatment groups based on mean changes and standard deviation to enable comparison of outcomes across studies that have used different outcome measures to enable them to be combined in meta-analyses; this method makes the calculation based on the size of the individual studies.

Wistar rat

A breed of non-transgenic rat that has been widely used for experimental studies.

γ-secretase

An intramembrane protease complex that cleaves the transmembrane amyloid precursor protein to produce amyloid-β.

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Corbett, A., Pickett, J., Burns, A. et al. Drug repositioning for Alzheimer's disease. Nat Rev Drug Discov 11, 833–846 (2012). https://doi.org/10.1038/nrd3869

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