INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease
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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: ), 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.
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These non-steroidal anti-inflammatory medications increased adverse events.
“Non-steroidal anti-inflammatory medication for AD, such as naproxen and celecoxib in older adults with a family history of AD over 1 to 3-years or aspirin 100mg for older people over 9.6 years did not decrease dementia risk, (362) although they did increase adverse events. (363)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [363]
The Results > Safety outcomes report more adverse events with naproxen than placebo (98% vs 89%; p = 0.015). The Discussion says naproxen and other NSAIDs can cause harm, but this trial does not establish increased adverse events specifically for the celecoxib and aspirin regimens also named in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPrevention studies of naproxen and celecoxib in patients at risk for preclinical Alzheimer disease failed to demonstrate any protective benefit.
“Prevention studies of naproxen and celecoxib in patients at risk for preclinical AD also failed to demonstrate any protective benefit (ADAPT-FS Research Group, 2015; Meyer et al., 2019).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Meyer et al., 2019
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“A subsequent 2-year, primary prevention trial [Impact of Naproxen Treatment in Presymptomatic Alzheimer’s Disease (INTREPAD)] has been used to compare the effects of naproxen and placebo on the Alzheimer Progression Score (APS) in 195 cognitively normal older persons with a positive family history of AD (226).”
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- Authors
- Meyer, P.-F., Tremblay-Mercier, J., Leoutsakos, J., Madjar, C., Lafaille-Maignan, M.-É., Savard, M., Rosa-Neto, P., Poirier, J., Etienne, P., Breitner, J., & for the PREVENT-AD Research Group
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- From the McGill Centre for Integrative Neuroscience, Montreal Neurological Institute (C.M.), and McGill University Research Centre for Studies in Aging (M.S., P.R.-N.), McGill University (P.-F.M., M.-E.L.-M., P.R.-N., J.P., P.E., J.B.); StoP-AD Centre (P.-F.M., J.T.-M., M.-E.L.-M., P.R.-N., J.P., P.E., J.B.), Douglas Mental Health University Institute Research Centre, Montréal, Canada; and John Hopkins University (J.L.), Baltimore, MD.
- Corresponding author
- Breitner, John
- ORCID
- Venue
- Neurology
- Published
- 2019-04-30
- Volume
- 92
- Issue
- 18
- Pages
- e2070-e2080
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC6512884
- OpenAlex
- W2928086185
- Cited by
- 113
- References
- 38
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 8 · 2023: 10 · 2022: 16 · 2021: 23 · 2020: 32 · 2019: 8
- FWCI
- 15.70
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-08-19)
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Neurology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- naproxen, Alzheimer's disease prevention, cognitive decline progression, cerebrospinal fluid biomarkers, adverse drug reactions, nonsteroidal anti-inflammatory drugs
- MeSH terms
- Aged, Alzheimer Disease, Anti-Inflammatory Agents, Non-Steroidal, Double-Blind Method, Female, Humans, Male, Middle Aged, Naproxen, Treatment Outcome, Disease Progression, Prodromal Symptoms
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