INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease

Neurology. 2019 Apr 30;92(18):e2070-e2080. doi: 10.1212/WNL.0000000000007232. Epub 2019 Apr 5.


Objective: To evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk.

Methods: Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195 AD family history-positive elderly (mean age 63 years) participants screened carefully to exclude cognitive disorder (NCT-02702817). These were randomized 1:1 to naproxen sodium 220 mg twice daily or placebo. Multimodal imaging, neurosensory, cognitive, and (in ∼50%) CSF biomarker evaluations were performed at baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS).

Results: Naproxen-treated individuals showed a clear excess of adverse events. Among treatment groups combined, the APS increased by 0.102 points/year (SE 0.014; p < 10-12), but rate of change showed little difference by treatment assignment (0.019 points/year). The treatment-related rate ratio of 1.16 (95% confidence interval 0.64-1.96) suggested that naproxen does not reduce the rate of APS progression by more than 36%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive presymptomatic AD.

Conclusions: In cognitively intact individuals at risk, sustained treatment with naproxen sodium 220 mg twice daily increases frequency of adverse health effects but does not reduce apparent progression of presymptomatic AD.

Classification of evidence: This study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of presymptomatic AD.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / prevention & control*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Disease Progression
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Naproxen / therapeutic use*
  • Prodromal Symptoms
  • Treatment Outcome


  • Anti-Inflammatory Agents, Non-Steroidal
  • Naproxen