Abstract
Alzheimer's disease (AD) represents a substantial unmet need, due to increasing prevalence in an ageing society and the absence of a disease modifying therapy. Epidemiological evidence shows a protective effect of non steroidal anti inflammatory (NSAID) drugs, and genome wide association studies (GWAS) show consistent linkage to inflammatory pathways; both observations suggesting anti-inflammatory compounds might be effective in AD therapy although clinical trials to date have not been positive.In this study, we use pathway enrichment and fuzzy logic to identify pathways (KEGG database) simultaneously affected in both AD and by NSAIDs (Sulindac, Piroxicam, Paracetamol, Naproxen, Nabumetone, Ketoprofen, Diclofenac and Aspirin). Gene expression signatures were derived for disease from both blood (n=344) and post-mortem brain (n=690), and for drugs from immortalised human cell lines exposed to drugs of interest as part of the Connectivity Map platform. Using this novel approach to combine datasets we find striking overlap between AD gene expression in blood and NSAID induced changes in KEGG pathways of Ribosome and Oxidative Phosphorylation. No overlap was found in non NSAID comparison drugs. In brain we find little such overlap, although Oxidative Phosphorylation approaches our pre-specified significance level.These findings suggest that NSAIDs might have a mode of action beyond inflammation and moreover that their therapeutic effects might be mediated in particular by alteration of Oxidative Phosphorylation and possibly the Ribosome pathway. Mining of such datasets might prove increasingly productive as they increase in size and richness.
Highlights
Alzheimer's disease (AD) is one of the largest single unmet medical needs today, due partly to the increasing numbers of cases in an ageing society [1,2], partly due to the absence of any disease modifying therapy [3] and mostly due to the very high cost of caring for people with dementia
In order to determine gene expression signatures that overlap between AD and non-steroidal anti-inflammatory drugs (NSAID) we used a three step process – first determining, from patient samples from blood and brain, the gene expression signature of AD [31,32,33,34] as well as the gene expression signature induced by NSAIDs in the Connectivity Map (CMap) database [35,36]; second determining the overlap in pathways induced by these drugs and that found in AD; and thirdly estimating the overlap expected by chance alone
The drug signatures were calculated for the most commonly prescribed NSAID drugs included in CMap study: Sulindac, Nabumetone, Ketoprofen, Piroxicam, Naproxen, Diclofenac, Paracetamol and Aspirin (Acetylsalicylic Acid)
Summary
Alzheimer's disease (AD) is one of the largest single unmet medical needs today, due partly to the increasing numbers of cases in an ageing society [1,2], partly due to the absence of any disease modifying therapy [3] and mostly due to the very high cost of caring for people with dementia. For more than three decades, epidemiological studies have shown that users of non-steroidal anti-inflammatory drugs (NSAID) are less likely to develop AD later in life, an effect observed most strongly after prolonged drug use [7,8,9]. More recent observational studies have largely replicated this finding [10,11,12,13,14,15], but to date there. Has been no translation of this observation into a usable therapy in randomised trials [16,17,18]. The mechanism of effect of the NSAIDs in reducing risk of AD remains uncertain, hampering attempts to translate the epidemiological finding to an effective therapy
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