Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects

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 intentionto-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.keywords: mild Alzheimer's disease, nilvadipine, exploratory analysis, cognitive decline, cerebrospinal fluid Aβ42/Aβ40 ratios Introduction:Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting nearly 5.3 million US citizens. By 2050, the prevalence of AD is expected to reach 13 million in the US alone and 100 million worldwide. The presence of amyloid plaques and neurofibrillary tangles in the brain are key hallmarks of AD (1-3) and are also accompanied by cerebrovascular disease, α-synuclein and TDP-43 deposits and inflammation (4-6). Recent clinical trials have shown that moderate AD patients, with established brain amyloid and tau pathologies, are unresponsive to anti-amyloid therapeutic approaches, although some trials have shown potential benefits in mild and early stage AD patients (7-11). As such, early and mild AD patient populations may be more appropriate for anti-amyloid and anti-tau approaches.Findings of the Systolic Hypertension in Europe (SYST-EUR) trial of 2400 participants showed that intervention with nitrendipine, a dihydropyridine (DHP) calcium channel blocker (CCB) similar in structure to nilvadipine, resulted in a reduction of AD incidence (12). A small clinical trial of nilvadipi...

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial

“…We also acknowledge Heather Langlois for assisting with data curation and analyses. This manuscript has been released as a Pre-Print at BioRxiv (44).…”