Our understanding of the pathophysiological mechanisms of Alzheimer’s disease (AD) remains relatively unclear; however, the role of neuroinflammation as a key etiological feature is now widely accepted due to the consensus of epidemiological, neuroimaging, preclinical and genetic evidence. Consequently, non-steroidal anti-inflammatories (NSAIDs) have been investigated in epidemiological and clinical studies as potential disease modifying agents. Previous epidemiological studies focused on incidence of AD and did not thoroughly parse the effects at the individual drug level. The therapeutic potential of modifying incidence has a number of limitations, and we now know that each NSAID subtype has a unique profile of physiological impacts corresponding to different therapeutic profiles for AD. Therefore, we utilized the AD Neuroimaging Initiative (ADNI) dataset to investigate how the use of common NSAIDs and paracetamol alter cognitive decline in subjects with mild cognitive impairment (MCI) or AD.

Negative binomial generalized linear mixed modelling was utilized to model the cognitive decline of 1619 individuals from the ADNI dataset. Both the mini-mental state examination (MMSE) and Alzheimer’s disease assessment scale (ADAS) were investigated. Explanatory variables were included or excluded from the model in a stepwise fashion with Chi-square log-likelihood and Akaike information criteria used as selection criteria. Explanatory variables investigated were APOE4, age, diagnosis (control, MCI or AD), gender, education level, vascular pathology, diabetes and drug use (naproxen, celecoxib, diclofenac, aspirin, ibuprofen or paracetamol).

The NSAIDs, aspirin, ibuprofen, naproxen and celecoxib did not significantly alter cognitive decline. However, diclofenac use was associated with slower cognitive decline (ADAS χ2=4.0, p=0.0455, MMSE χ2=4.8, p=0.029). Paracetamol use was associated with accelerated decline (ADAS χ2=6.6, p=0.010, MMSE χ2=8.4, p=0.004). The APOE4 allele was associated with accelerated cognitive deterioration (ADAS χ2=316.0, p<0.0001, MMSE χ2=191.0, p<0.0001).

This study thoroughly investigated the effects of common NSAIDs and paracetamol use on cognitive decline in MCI and AD subjects. Most common NSAIDs did not alter cognitive decline. However, diclofenac use was associated with slowed cognitive deterioration, providing exciting evidence for a potential disease modifying therapeutic. Conversely, paracetamol use was associated with accelerated decline; which, if confirmed to be causative, would have massive ramifications for the recommended use of this prolific drug.