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Table 2 Putative clinical and biological markers of the distinct stages in the AD continuum (from normal cognition to dementia), and respective therapeutic interventions (clinically supported therapies and potential interventions with candidate drugs/strategies that still require experimental validation)

From: Diagnosis and biomarkers of predementia in Alzheimer's disease

Clinical stage Underlying pathological mechanisms Putative clinical and biological markers Potential therapeutic interventions
Asymptomatic (pre-clinical AD) Intracerebral accumulation of amyloid-β - CSF concentrations of Aβ42 - Cognitive reserve (education and level of intellectual functioning)
   - Molecular imaging (PiB-PET) - Lifestyle changes (nutrition, physical fitness, reduction of stress)
   - Autossomal dominant mutation(APP, PS1, PS2 genes) - Management of underlying factors (cardiovascular risk factors, toxic and comorbid conditions)
Prodromal (pre-dementia AD) Aβ-related pathology(amyloid cascade) - Episodic memory impairment(amnestic MCI) - Anti-amyloid therapy:
* immunotherapy anti-Aβ
* modulation of β- and γ-secretase
* anti-fibrillization agents and chelators
   - CSF concentrations of Aβ42  
   - Molecular imaging (PiB-PET)  
   - Autossomal dominant mutation(APP, PS1, PS2 genes)  
  Tau-related pathology (neurodegeneration) - Multiple-domain amnestic MCI - All above
   - CSF concentrations of Tau(total and phosphorylated Tau) - Neuroprotective approaches(antioxidants, anti-inflammatory drugs)
   - Brain metabolism (FDG-PET) - Tau-related therapies(GSK inhibitors, lithium)
   - Medial temporal lobe atrophy(volumetric MRI, VBM) - Neurorestorative approaches(NGF, BDNF, stem cells)
Clinical dementia Neuritic plaquesNeurofibrillary tangles - Neuropsychological tests - Antidementia drugs (cholinesterase inhibitors, memantine)
   - Functional assessment - Cognitive training
   - Structural imaging (CT/MRI) - Functional rehabilitation (ADLs)
   - Neuropathology - Psychoeducation (caregivers)
  1. AD, Alzheimer's disease; MCI, mild cognitive impairment; Aβ, amyloid-beta peptide; CSF, cerebrospinal fluid; APP, amyloid precursor protein; PS, pre-senilins 1 and 2; PET, positron emission tomography; PiB, Pittsburgh compound B; FDG, fluorodeoxyglucose; CT, computerized tomography scan; MRI, magnetic resonance imaging; VBM, voxel-based morphometry.