Abstract
BackgroundTreatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores.MethodsFor this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples.ResultsCompared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels.ConclusionsCollectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders.Trial registrationClinicalTrials.gov NCT01504854
Highlights
Treatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol attenuates progressive declines in cerebrospinal fluid (CSF) Aβ40 levels and activities of daily living (ADL) scores
The level of CSF MMP9 was significantly reduced in the placebo group between baseline and 52 weeks (Fig. 1a), and MMP9 was further reduced (48%) at 52 weeks in the resveratrol group
The CSF levels of macrophage-derived chemokine (MDC) (Fig. 1c) and fibroblast growth factor (FGF)-2 (Fig. 1d) were increased after 52 weeks of resveratrol treatment compared to baseline, with no changes in these molecules in plasma (Table 1)
Summary
Treatment of mild-moderate Alzheimer’s disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores. Despite the phase 2 trial being underpowered to detect clinical benefits, resveratrol attenuated decline in the Alzheimer’s Disease Cooperative StudyActivity of Daily Living (ADCS-ADL) score during the 12month study. Aging is a major risk factor for cancer, and fewer cancers were found in the resveratrol-treated group (one versus seven cancers in six participants in the placebo group) These data support the notion that targeting molecular mechanisms of aging may point to therapeutic strategies that postpone or prevent diseases of aging—in parallel. With proven safety and suggestions of efficacy in the phase 2 trial, the putative benefits of resveratrol and other sirtuin activator compounds (STACs) should be further examined in clinical studies
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