Figure 1. Biomarkers of Alzheimer’s disease.

Hypothesized changes in CSF biomarkers in relation to the time course of pathological and clinical stages, and other biomarker modalities. The clinical stages of AD, marked by progressive dementia described as very mild/MCI, mild, moderate, and severe, correspond with the CDR scores of 0.5, 1, 2, and 3, respectively. These stages are associated with abundant amyloid plaques (red line), the gradual accumulation of neurofibrillary tangles (blue line), synaptic and neuronal loss in certain brain regions (green line). In the preclinical stage of AD, Aβ₄₂ peptide forms amyloid plaques in the brains of nondemented individuals (CDR 0) for approximately 10–20 years, and damages neuronal processes and synapses. Eventually, dramatic neuronal losses occur in association with dementia onset. AD biomarker research seeks to capture these changes in the brain, which might be useful for diagnosis and prognosis during this preclinical phase of AD, before irreversible neuronal loss occurs. These changes can be measured by biochemical examination of CSF, and/or a variety of radiological imaging modalities (e.g., CT, MRI, and PIB PET). The most promising CSF biomarkers to date have been Aβ₄₂ and tau species, which show diagnostic and prognostic utility. BACE1 as an indicator of Aβ production warrants further study, as do panels of inflammatory markers and markers of oxidative stress. Genetic variations (e.g., SNPs) may also be considered biomarkers that allow the earliest possible estimation of risk.

Aβ: Amyloid-β;AD: Alzheimer’s disease; BACE: β-site amyloid precursor protein-cleaving enzyme; CDR: Clinical Dementia Rating; CSF: Cerebrospinal fluid; CT: Computed tomography; MCI: Mild cognitive impairment PIB: Pittsburgh compound-B; p-tau: Phosphorylated tau; SNP: Single nucleotide polymorphism.

Adapted with permission from [83].