Abstract
Background: We explored whether the effects of nilvadipine on cognition were influenced by baseline Alzheimer's disease (AD) severity. Methods: Exploratory analyses were performed on the modified intention-to-treat (mITT) dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in very mild, mild and moderate AD subjects. The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS), an outcome measure recently developed to detect treatment responses in subjects with prodromal AD. Cerebrospinal fluid (CSF) biomarkers Aβ38, Aβ40, Aβ42, total tau and P181 tau were measured in a subset of samples (n = 55). Regression analyses were adjusted for potential confounders and effect modifiers in order to examine the interactive effects of nilvadipine and AD severity on cognitive outcomes over 78-weeks. Results: Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed greater decline on the ADAS-Cog 12. Also in very mild AD, a beneficial effect (as measured by ADCOMS), was detected in the nilvadipine treated group. Therapeutic effects of nilvadipine were also observed for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. CSF Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Conclusion: These data suggest that very mild AD subjects benefited from nilvadipine and that future clinical trials of nilvadipine in this population are required to confirm these findings. Clinical Trial registration ID #NCT02017340
