Detection of Alzheimer Disease Pathology in Patients Using Biochemical Biomarkers: Prospects and Challenges for Use in Clinical Practice

Abstract

Background: Thirty-four years ago, amyloid-β 1-42 peptide was identified in amyloid plaques from brain tissue obtained from patients with Alzheimer disease (AD) and Down syndrome. This finding led to development of immunoassays for this marker of amyloid plaque burden in cerebrospinal fluid (CSF) approximately 10 years later. Subsequently, research immunoassays were developed for total - protein and - phosphorylated at the threonine 181 position. Subsequent studies documented the clinical utility of these biomarkers of amyloid plaque burden or - tangle pathology in cohorts of living patients. Content: We describe the following: (a) clinical utility of AD biomarkers; (b) measurement challenges, including development of mass spectrometry-based reference methods and automated immunoassays; (c) development of appropriate use criteria (AUC) guidelines for safe/appropriate use of CSF testing for diagnosis of AD developed by neurologists, a neuroethicist, and laboratorians; (d) a framework, sponsored by the National Institute of Aging-Alzheimer's Association (NIA-AA), that defines AD on the basis of CSF and imaging methods for detecting amyloid plaque burden, - tangle pathology, and neurodegeneration. This framework's purposewasinvestigative but has important implications for future clinical practice; (e) recognition of copathologies in AD patients and challenges for developing methods to detect these in living patients. Summary: The field can expect availability of validated research tools for detection of AD pathology that support clinical treatment trials of disease-modifying agents and, ultimately, use in clinical practice. Validated methods are becoming available for CSF testing; emergence of validated methods for AD biomarkers in plasma can be expected in the next few years.