Consistent treatment with twice-daily naproxen sodium at 220 mg per dose increases the frequency of adverse health effects in cognitively intact individuals at risk for presymptomatic Alzheimer disease (AD) and does not appear to reduce the progression of the disease, according to study results published in Neurology.

A sample of cognitively intact patients at risk for presymptomatic AD and enrolled in the 2-year Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer’s Disease (INTREPAD; identifier: NCT02702817) study were enrolled in the analysis (n=195). Participants were considered at risk if they were older (mean age of sample, 63 years) and had a positive family history of AD. The researchers randomly assigned patients 1:1 to either twice-daily naproxen sodium at 220 mg per dose (n=102) or placebo (n=93).

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Participants underwent multimodal imaging, neurosensory, cognitive, and cerebrospinal fluid (CSF) biomarker evaluations at baseline, and 3, 12, and 24 months. In a modified intent-to-treat analysis, a total of 160 participants who stayed on treatment through first follow-up were included. The rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS) comprised the primary outcome.

Individuals who were treated with naproxen had a greater number of adverse events compared with participants treated with placebo. A greater percentage of participants treated with naproxen experienced constipation (19% vs 6%; P =.011), dyspnea (23% vs 11%; P =.028), heartburn (30% vs 18%; P =.05), hypertension (19% vs 9%; P =.04), and petechiae (12% vs 2%; P =.009).

There was no association between naproxen and a reduced rate of APS progression of >36% (treatment-related rate ratio, 1.16; 95% CI, 0.64-1.96). There was no treatment effect on CSF, cognitive, or neurosensory biomarker indicators of presymptomatic AD progression. Results on the University of Pennsylvania Smell Identification Test noted a trend toward harm with naproxen (β = −0.320; SE = 0.196; 95% CI −0.704 to 0.064; P =.102).

A limitation of the study included the small sample size.

“In all events, this work has left us with extreme pessimism regarding any possible role of nonsteroidal anti-inflammatory drugs (NSAIDs) in AD prevention,” the researchers concluded. “Instead, our results may suggest reconsideration of inflammatory diseases (or a proinflammatory diathesis) as a possible explanation for the reduced AD incidence among NSAID users in observational studies.”


Meyer PF, Tremblay-Mercier J, Leoutsakos J, et al; PREVENT-AD research group. INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease [published online April 5, 2019]. Neurology. doi:10.1212/WNL.0000000000007232