O4‐11‐03: A PROINFLAMMATORY ENDOPHENOTYPE PREDICTS TREATMENT RESPONSE IN A MULTICENTER TRIAL OF NSAIDS IN AD
Sid E. O’Bryant, Robert A. Rissman, Constantine George Lyketsos · Alzheimer s & Dementia · 2014
Epidemiological studies suggest that reducing inflammation through use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased risk of Alzheimer 's disease (AD). However, a recent multicenter clinical trial in mild-moderate AD conducted by the Alzheimer's Disease Cooperative Study (ADCS) failed to demonstrate clinical benefit of NSAID treatment over 12 months. Although this result may the associated with dosage or disease stage, it is our hypothesis that a proinflammatory endophenotype (PIE) at baseline is might identify a subgroup of patients who benefited from NSAID treatment. Baseline plasma samples were provided by the ADCS biospecimen bank from 209 participants. A total of 156 participants had viable samples for assay as well as available relevant data for inclusion. Biobank analysis of CRP and TNFα were conducted via electrochemiluminescence (ECL) using the Meso Scale Discovery platform. Plasma levels of CRP and TNFα were utilized to define the PIE based on a priori criteria. The breakdown of the PIE by treatment arm was as follows: Placebo - low = 9.5%, middle = 81%, high = 9.5%; Naproxen - low = 10%, middle = 74%, high = 16%; Rofecoxib - low = 9%, middle = 78%, high = 13%. In these analyses we compared outcomes in patients with different levels of PIE at baseline. In the high PIE group, those on naproxen had significantly less decline in MMSE scores over 12 months, compared to those on placebo (partial eta squared = 0.58; F[1,6] = 8.2, p=0.03; observed power =0.7). Indeed, 63% of the high PIE patients on naproxen remained stable or improved over 12 months, compared to 25% on placebo. Patients with a low PIE on naproxen appeared to decline faster than those on placebo group. There was no apparent treatment effect for the rofecoxib group. Baseline levels of a PIE identify a subgroup of participants that benefited from this clinical trial. As 10% of patients having a baseline high PIE, this profile may identify a substantial number of patients suffering from AD that benefit from naproxen treatment. This same profile may identify a subset of patients more likely to become worse with such treatment.