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

Abstract

In the article, “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease”, Meyer et al. reported that low-dose naproxen did not significantly reduce the progression of a composite indicator of presymptomatic Alzheimer Disease (AD)—the Alzheimer Progression Score (APS)—in a 2-year double-blind randomized placebo-controlled trial that enrolled 195 cognitively intact elderly participants with a family history of AD. In response, Dr. Ashford posits that the observed epidemiologic association of nonsteroidal anti-inflammatory drugs (NSAIDs) with decreased risk of AD may be related to the effect of these drugs on gamma-secretase rather than on inflammation, citing previous work showing that flurbiprofen and ibuprofen lower amyloidogenic Abeta42 independently of cyclooxygenase activity. He postulates that several years of treatment may be required to observe a benefit and wonders whether ibuprofen may be a better drug to test than naproxen. He also highlights the need for better tools to more accurately assess treatment effects in early AD. Responding to these comments, Drs. Breitner et al. noted that a meta-analysis of 6 prospective studies showed no significant differences in apparent risk modification of AD between gamma secretase-modifying and non-gamma secretase-modifying NSAIDS and suggested no difference between exposure to naproxen vs ibuprofen. Although they acknowledge that INTREPAD lacked an initially estimated degree of power, they note that the APS captured significant progression of apparent AD signs over the course of the trial and allowed a reasonably precise estimate of a lack of treatment effect, with naproxen also having no benefit on any of the APS components. With the largely unimpressive results of antiamyloid treatment strategies to date in AD, interest in alternative therapeutic targets, including anti-inflammatory strategies, is likely to continue growing in the coming years. In the article, “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease”, Meyer et al. reported that low-dose naproxen did not significantly reduce the progression of a composite indicator of presymptomatic Alzheimer Disease (AD)—the Alzheimer Progression Score (APS)—in a 2-year double-blind randomized placebo-controlled trial that enrolled 195 cognitively intact elderly participants with a family history of AD. In response, Dr. Ashford posits that the observed epidemiologic association of nonsteroidal anti-inflammatory drugs (NSAIDs) with decreased risk of AD may be related to the effect of these drugs on gamma-secretase rather than on inflammation, citing previous work showing that flurbiprofen and ibuprofen lower amyloidogenic Abeta42 independently of cyclooxygenase activity. He postulates that several years of treatment may be required to observe a benefit and wonders whether ibuprofen may be a better drug to test than naproxen. He also highlights the need for better tools to more accurately assess treatment effects in early AD. Responding to these comments, Drs. Breitner et al. noted that a meta-analysis of 6 prospective studies showed no significant differences in apparent risk modification of AD between gamma secretase-modifying and non-gamma secretase-modifying NSAIDS and suggested no difference between exposure to naproxen vs ibuprofen. Although they acknowledge that INTREPAD lacked an initially estimated degree of power, they note that the APS captured significant progression of apparent AD signs over the course of the trial and allowed a reasonably precise estimate of a lack of treatment effect, with naproxen also having no benefit on any of the APS components. With the largely unimpressive results of antiamyloid treatment strategies to date in AD, interest in alternative therapeutic targets, including anti-inflammatory strategies, is likely to continue growing in the coming years.