A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease
Patrizio Pasqualetti1,2, Cristina Bonomini3, Gloria Dal Forno4, Luca Paulon1, Elena Sinforiani5, Camillo Marra6, Orazio Zanetti3 and Paolo Maria Rossini3,7
1Medical Statistics & Information Technology, Fatebenefratelli Association for Research, Isola Tiberina, Rome, 2Casa di Cura San Raffaele Cassino e IRCCS San Raffaele Pisana, Rome, 3Alzheimer Unit, IRCCS Centro S. Giovanni di Dio - FBF, Brescia, Italy, 4Department of Neurology, Medical College of Wisconsin, Milwaukee, USA, 5Alzheimer Unit, Fondazione Istituto Neurologico C. Mondino, Pavia, Italy, 6Neuropsychological Unit, Department of Neuroscience, Catholic University, Rome, 7Department of Neurology, University Campus Bio-Medico, Rome, Italy

Abstract

Background and Aims: Epidemiological studies have examined the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Alzheimer’s disease (AD). Recently, a variety of experimental studies indicates that a subset of NSAIDs, such as ibuprofen or flurbiprofen, also have Aβ-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. In this trial, we evaluated whether the non-selective NSAID ibuprofen slows disease progression in patients with mild to moderate AD. Methods: This was a 12-month multicenter, randomized, double-blind, placebo-controlled, parallel group trial. Participants with mild-moderate AD (Mini-Mental State Examination score >15, <26; Clinical Dementia Rating= 0.5-1), 65 years or older, with reliable caregivers, were recruited between April 2003 and September 2004. Seven AD Outpatient Treatment Centers screened 530 patients, 132 of whom were enrolled. Intervention consisted of 400 mg ibuprofen twice a day or placebo, together with 20 mg once a day of esomeprazol, or placebo. The primary measure was any one-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary measures included changes in MMSE, CDR, Basic and Instrumental Activities of Daily Living scales, and Neuropsychiatric Inventory (NPI). Results: Fifty-one patients (77%) in the ibuprofen vs 46 (70%) in the placebo group completed the protocol (p>0.20). In intention-to-treat analysis, ADAS-Cog score worsening was similar in the two groups (p=0.951, treatment difference=0.1, CI -2.7; 2.9). No differences were found for any secondary outcomes. In a subsample of genotyped patients, ApoE ε4 carriers treated with ibuprofen (n=27) were the only group without significant cognitive decline. Conclusions: Ibuprofen, if used for relatively short periods of time and although well tolerated thanks to gastroprotection, does not seem to be effective in tertiary prevention of mild-moderate AD. Our results suggest the need to examine whether differences in the response to NSAIDs exist, based on ApoE ε4 carrier status. (Aging Clin Exp Res 2009; 21: 102-110) ©2009, Editrice Kurtis

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