A prospective population-based cohort study has revealed that long-term use of nonsteroidal anti-inflammatory drugs is associated with a decreased risk of dementia. Duration, rather than dosage, emerged as a key factor in potential protective effects.
Researchers from the Rotterdam Study followed 11,745 participants without dementia (59.5% female, mean age 66.2 years) for an average of 14.5 years and examined the relationship between nonsteroidal anti-inflammatory drug (NSAID) use and dementia risk using pharmacy dispensing records dating back to 1991.
In their study published in the Journal of the American Geriatrics Society, M. Arfan Ikram, MD, of the Department of Epidemiology at Erasmus University Medical Center in the Netherlands, and colleagues found that long-term NSAID use (defined as greater than 24 months) was associated with a 12% reduction in dementia risk (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.91) compared with nonuse. Conversely, short-term use of less than 1 month and intermediate-term use of 1 to 24 months showed a slight increased risk (HR = 1.04, 95% CI = 1.02–1.07 and HR = 1.04, 95% CI = 1.02–1.06, respectively).
These findings suggest "that prolonged rather than intensive exposure to anti-inflammatory medication may hold potential for dementia prevention," the researchers concluded.
Notably, the cumulative dose of NSAIDs did not demonstrate a dose-response relationship with dementia risk reduction. When researchers analyzed NSAIDs by their amyloid-β lowering properties, they found that NSAIDs without known effects on amyloid-β showed a stronger protective association (HR = 0.79, 95% CI = 0.74–0.85) than those with amyloid-lowering properties (HR = 0.89, 95% CI = 0.85;0.93). Examples of nonamyloid-β lowering NSAIDs included naproxen, rofecoxib, and meloxicam.
The association was particularly pronounced for clinical Alzheimer's disease compared with all-cause dementia (HR = 0.79, 95% CI = 0.76–0.83). Additionally, the protective effect was observed only in participants without the APOE-ε4 allele (HR = 0.86, 95% CI = 0.82–0.90), while APOE-ε4 carriers showed no significant benefit (HR = 1.02, 95% CI = 0.95–1.11).
The researchers conducted sensitivity analyses that excluded the 2 years immediately prior to dementia diagnosis to account for potential prodromal changes in NSAID use. Results remained consistent, which indicated the findings were not influenced by these changes.
The Rotterdam Study represents one of the most comprehensive examinations of NSAID use and dementia risk to date, with 30 years of data on medication use and rigorous dementia surveillance. During the follow-up period, 9,520 participants (81.1%) used NSAIDs at some point, and 2,091 developed dementia.
The researchers controlled for numerous potential confounding factors, including lifestyle factors, comorbidities, and comedication use. Adjustments included education, smoking, alcohol use, body mass index, blood pressure, and cholesterol levels.
They emphasized that while their findings highlight the potential role of anti-inflammatory mechanisms in dementia prevention, they do not justify recommending long-term NSAID treatment due to known adverse effects. NSAIDs are currently listed as potentially inappropriate medications for older adults according to the Beers criteria.
These results contrast with randomized controlled trials that showed no benefit from NSAID use, potentially due to shorter treatment durations (median = 1.5-1.8 years) or inclusion of participants with already advanced pathology.
No competing interests were declared.
