Plasma Biomarkers of Alzheimer's Disease: A Review of Available Assays, Recent Developments, and Implications for Clinical Practice

Recently, low-sensitive plasma assays have been replaced by new ultra-sensitive assays such as single molecule enzyme-linked immunosorbent assay (Simoa), the Mesoscale Discovery (MSD) platform, and immunoprecipitation-mass spectrometry (IP-MS) with higher accuracy in the determination of plasma biomarkers of Alzheimer's disease (AD). Despite the significant variability, many studies have established in-house cut-off values for the most promising available biomarkers. We first reviewed the most used laboratory methods and assays to measure plasma AD biomarkers. Next, we review studies focused on the diagnostic performance of these biomarkers to identify AD cases, predict cognitive decline in pre-clinical AD cases, and differentiate AD cases from other dementia. We summarized data from studies published until January 2023. A combination of plasma A beta(42/40) ratio, age, and APOE status showed the best accuracy in diagnosing brain amyloidosis with a liquid chromatography-mass spectrometry (LC-MS) assay. Plasma p-tau217 has shown the best accuracy in distinguishing A beta-PET+ from A beta-PET- even in cognitively unimpaired individuals. We also summarized the different cut-off values for each biomarker when available. Recently developed assays for plasma biomarkers have undeniable importance in AD research, with improved analytical and diagnostic performance. Some biomarkers have been extensively used in clinical trials and are now clinically available. Nonetheless, several challenges remain to their widespread use in clinical practice.