Long-term non-steroidal anti-inflammatory drug (NSAID) use and dementia or cognitive decline risk in adults over 50 based on epidemiological studies: A narrative review

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Inflammation plays a critical role in the pathogenesis of Alzheimer’s disease (AD) and related dementias, highlighting the need for investigations into the neuroprotective potential of non-steroidal anti-inflammatory drugs (NSAIDs). This review synthesizes epidemiological evidence published between 2010 and 2025 to examine associations between long-term NSAID use and the risk of cognitive decline or dementia among adults aged 50 years and older. Ultimately, 40 studies, including 29 cohort investigations and 11 systematic reviews or meta-analyses, with a combined sample size exceeding 300,000 participants were analyzed. Notably, available evidence suggests that low-dose aspirin was consistently correlated with reduced AD incidence (relative risk reductions from 25% to over 70%) and slower cognitive deterioration. In contrast, findings for non-aspirin NSAIDs (ibuprofen, naproxen, cyclooxygenase-2 [COX-2] inhibitors) were heterogeneous. Key modifiers of NSAID efficacy included age at NSAID initiation (e.g., more pronounced benefits when started before age 65), cumulative dose, and cardiovascular comorbidities. Moreover, varying safety profiles had been noted, as evidenced by elevated bleeding risk with aspirin-carrying and increased gastrointestinal adverse events with selective COX-2 inhibitors. Despite promising observational results, randomized trials have failed to confirm the cognitive benefits of NSAIDs, underscoring the need for mechanistic research and well-designed interventional studies. We therefore advocate for stratified clinical trials that consider NSAID type, dosage, timing, and patient genotype to clarify its therapeutic utility.