Resveratrol for Alzheimer's disease

Abstract

The amyloid hypothesis suggests that the progressive accumulation and deposition of central nervous system (CNS) amyloid with aging is the proximate cause of Alzheimer's disease (AD). Thus, targeting molecular mechanisms of aging may be a viable treatment approach. Caloric restriction prevents diseases of aging, including AD, in animal models, perhaps by activation of sirtuins. The sirtuins (e.g., mammalian SIRT1) are deacetylases that link energy balance (NAD⁺ /NADH) to regulation of gene transcription. Resveratrol is a potent activator of SIRT1, and thus may mimic caloric restriction to prevent diseases of aging. We conducted a randomized, double-blind, placebo-controlled, phase II trial of resveratrol for individuals with mild-to-moderate AD. Resveratrol (1) is detectable in cerebrospinal fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves blood-brain barrier integrity, and (5) modulates the CNS immune response. Further studies are needed to determine the safety and efficacy of resveratrol and the validity of this approach in the treatment and prevention of AD and other diseases of aging.

Keywords: Alzheimer's disease; amyloid; polyphenol; resveratrol; sirtuin.

Figure 1

Alzheimer’s disease (AD) as a metabolic disorder. Risk factors for mild cognitive impairment (MCI) and AD with aging include caloric excess and sedentary lifestyle, leading to insulin and glucose dysregulation. In contrast, exercise and caloric restriction (or intermittent fasting) may delay or prevent cognitive decline with aging. Prodromal AD refers to individuals who are cognitively intact but have a positive AD biomarker. Resveratrol may mimic effects of caloric restriction by activation of sirtuins—deacetylases that link energy balance (via NAD⁺/NADH regulation) to altered gene transcription (via epigenetics). Thus, although classically considered as non-modifiable risk factors for AD, genetics and aging may be modifiable.

Figure 2

(A) Investigational agents for Alzheimer’s disease (AD) targeting amyloid. The majority of phase II/II trials in progress either promote Aβ clearance (active and passive immunotherapy) or inhibit Aβ generation (BACE1 inhibitors). Outcome measures for AD trials include cognitive, functional, and behavioral measures; MRI and PET neuroimaging; and cerebrospinal fluid (CSF) proteomics (especially Aβ, tau, and phospho-tau).

Figure 2

(A) Investigational agents for Alzheimer’s disease (AD) targeting amyloid. The majority of phase II/II trials in progress either promote Aβ clearance (active and passive immunotherapy) or inhibit Aβ generation (BACE1 inhibitors). Outcome measures for AD trials include cognitive, functional, and behavioral measures; MRI and PET neuroimaging; and cerebrospinal fluid (CSF) proteomics (especially Aβ, tau, and phospho-tau).