Biomarkers in translational research of Alzheimer’s Disease

Abstract

The identification and characterization of amyloid-β (Aβ) and tau as the main pathological substrates of Alzheimer’s disease (AD) have driven many efforts in search for suitable biomarkers for AD. In the last decade, research in this area has focused on developing a better understanding of the principles that govern protein deposition, mechanisms that link aggregation to toxicity and neuronal death, and a better understanding of protein dynamics in brain tissue, interstitial fluid and CSF. While Aβ and tau represent the two key pathological mediators of disease, other aspects of this multifaceted disease (e.g. oxidative stress, calcium-mediated toxicity, and neuroinflammation) are being unraveled, with the hope to develop a more comprehensive approach in exploring disease mechanisms. This has not only expanded possible areas for disease-modifying therapies, but has also allowed the introduction of novel, and potentially useful, fluid and radiological markers for the presence and progression of AD pathology. There is no doubt that the identification of several fluid and imaging biomarkers that can reliably detect the early stages of AD will have great implications in the design of clinical trials, in the selection of homogenous research populations, and in the assessment of disease outcomes. Markers with good diagnostic specificity will aid researchers in differentiating individuals with preclinical and probable AD from individuals who do not have AD pathology or have other dementing disorders. Markers that change with disease progression may offer utility in assessing the rates of disease progression and the efficacy of potential therapeutic agents on AD pathology. For both of these purposes, CSF Aβ42, amyloid imaging, and CSF tau appear to be very good markers of the presence of AD pathology as well as predictive of who will progress from MCI to AD. Volumetric MRI is also good at separating individuals with MCI and AD from controls and is predictive of who will progress from MCI to AD. Perhaps the most important role biomarkers will have, and the most needed at this time, lies in the identification of individuals who are cognitively normal, and yet have evidence of AD pathology (i.e. preclinical AD). Such individuals, it appears, can be identified with CSF Aβ42, amyloid imaging, and CSF tau. Such individuals are the most likely to benefit from future disease modifying/prevention therapies as they become available, and therefore represent the population in which the field can make the biggest therapeutic impact.