Chapter 6 - Peripheral Fluid-Based Biomarkers of Alzheimer’s Disease

Abstract

It is commonly believed that Alzheimer’s disease (AD) is an abnormality of the aging brain; however, a growing body of literature supports the notion that AD is a systemic disease with associated dysfunction in metabolic, oxidative, inflammatory, and biochemical pathways that can be detected in peripheral body fluids, such as blood, urine, and saliva. These observations have led researchers to investigate and develop assays of peripheral AD biomarkers that require minimally invasive blood, saliva, and urine samples. Because cerebrospinal fluid (CSF) can only be collected by lumbar puncture, CSF-based biomarkers of AD may not lend themselves to diagnostic screening applications or routine use in elderly patients. In contrast, blood-based AD biomarkers may provide a better, less invasive alternative for AD screening, early diagnosis of AD, and repeat testing to assess treatment efficacy. Two common approaches to discovering and developing peripheral fluid-based AD biomarkers are lipidomics and proteomics. The best researched AD blood-based biomarkers are the Aβ peptides Aβ1–40 and Aβ1–42; tau proteins; inflammatory proteins C-reactive protein (CRP), antichymotrypsin, macroglobulin, interleukins, TNF-α, complement factors, homocysteine, clusterin, APOE, and serum amyloid protein (SAP). The testing procedures, including collection and storage of blood samples, for each of these biomarkers vary widely, and the accuracy, sensitivity, and specificity of blood-based AD biomarkers have, until recently, been lower than those of CSF biomarkers. In addition to providing a review of all peripheral fluid biomarkers, this chapter summarizes recent findings of cross-sectional and longitudinal studies of blood plasma AD biomarkers, crosscorrelation of blood plasma AD biomarkers with other AD biomarkers, and possible application of blood plasma AD biomarkers in clinical trials of AD therapeutics. There is a critical need for standardization of analytical methodologies, sample collection procedures, and reference standards for all peripheral fluid-based AD biomarkers to improve interlaboratory variation and sensitivity and specificity.