CommentaryAlzheimer's Disease

Testing the Right Target and Right Drug at the Right Stage

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Science Translational Medicine  30 Nov 2011:
Vol. 3, Issue 111, pp. 111cm33
DOI: 10.1126/scitranslmed.3002609

Figures

  • Fig. 1.

    Optimal stage for intervention? Shown is a scheme of the proposed stages of AD with potential prevention and treatment targets. We have depicted the hypothetical dynamic trajectories of currently available biomarkers of the AD pathophysiological process over the clinical course of the disease by plotting biomarker measurements (from normal to abnormal ranges) on the y-axis versus the defined clinical stages of AD on the x-axis [adapted from Jack et al. 2010 (29), with permission]. Primary prevention trials would occur in individuals who do not yet have evidence of AD pathology, whereas secondary prevention trials would occur in individuals who have evidence of early pathology, as assessed with AD biomarkers, but do not yet have clinically evident symptoms, meeting criteria for MCI. Red, amyloid β accumulation (CSF, PET); yellow, synaptic dysfunction (FDG-PET, fMRI); turquoise, tau-mediated neuronal injury (CSF); blue, brain structure (volumetric MRI); purple, cognition; brown, clinical function. [Adapted from Jack et al. 2010 (29), with permission]

    CREDIT: B. STRAUCH/SCIENCE TRANSLATIONAL MEDICINE

Tables

  • Table 1.

    Current and future disease-modifying therapeutic targets for AD.

    Decrease Aβ production
    • β-secretase inhibition
    • γ-secretase inhibition or modulation
    • α-secretase enhancement
    Decrease Aβ aggregation
    • Decrease metal ion–mediated fibrilization
    • Decrease oligomer formation via reduction of Aβ monomers
    • Decrease plaques by blocking β-pleated sheet formation
    Increase Aβ degradation
    • Insulin-degrading enzyme (IDE) activation
    • Neprilysin activation
    Increase Aβ clearance
    • “Active” vaccination with truncated Aβ peptide
    • Passive immunization with monoclonal antibody against Aβ epitope
    • Passive immunization with antibody against specific confirmational forms of Aβ (such as oligomers, protofibrils, or plaque)
    Decrease tau and neurofibrillary tangle formation
    • Prevent tau hyperphosphorylation
    • Decrease tau aggregation
    • Stabilize microtubules
    • Active and passive immunization against tau
    Neuroprotection or neuroregeneration
    • Antioxidant and other agents to preserve metabolic and/or mitochondrial function
    • Antiapoptotic agents
    • Decrease inflammatory damage
    • Nerve growth factor enhancement
    • Stem cell–based neuron replacement

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