Abstract
Background: This study explores whether the baseline severity of Alzheimer’s disease (AD) subjects in the NILVAD trial modified the effects of nilvadipine, a dihydropyridine calcium channel blocker shown to target multiple aspects of AD pathology in preclinical studies. Methods: Exploratory analyses were performed on the modified intention-to-treat (mITT) dataset (n = 497) to examine the response to nilvadipine in very mild, mild and moderate AD subjects. The main outcome measures included total scores and subscales of the Alzheimer’s Disease Assessment Scale Cognitive 12 (ADAS-Cog 12) and the Clinical Dementia Rating Scale sum of boxes (CDR-sb). All statistical analyses were adjusted for the confounding effects of the apolipoprotein E (APOE) ε4 allele and education and effect modification by gender in order to examine the interactive effects of nilvadipine and AD severity over the 78-week study period. Results: Compared to their respective placebo controls, nilvadipine-treated very mild AD subjects showed lower decline whereas nilvadipine-treated moderate AD subjects showed greater decline on the ADAS-Cog 12 scores. The therapeutic effects of nilvadipine were observed for the memory trait (which included immediate word recall and delayed recall) in very mild AD subjects and the language trait (which included spoken language, word finding difficulties and language comprehension) in mild AD subjects. Moderate AD subjects on nilvadipine showed decline on several aspects of cognition. Conclusion: These exploratory analyses suggest that nilvadipine may have cognitive benefits for very early AD subjects. Future clinical trials of nilvadipine focused on such individuals are required to confirm these findings.