Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances

Abstract

Discovery and development of clinically useful biomarkers for Alzheimer’s disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-β (Aβ) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aβ and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aβ and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aβ peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.

Plasma p-tau181/Aβ1-42ratio predicts Aβ-PET status and correlates with CSF-p-tau181/Aβ1-42and future cognitive decline

“…The AUCs improved as the CL threshold was increased. This compares favourably with other Simoa Aβ and pTau analyses whose AUCs range between 0.66 to 0.88 [11, 31-33], and is similar to AUCs for the only current FDA-approved plasma test for determining amyloid positivity, which in a cohort of predominately CDR-SOB 0 had an AUC of 0.88 and 0.94 when run without and with other covariates of age and APOE ε 4 on a mass spectrometry platform [34]. In the AIBL study cohort, addition of APOE ε 4, sex, age and PET tracer only marginally improved the performance of the plasma test, potentially reducing the need for measuring other parameters when used as a trial-screening tool.…”

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke

“…Additional promising approaches to further improve PSCI prediction include assessment of co-occurring Alzheimer pathology (e.g. using cerebrospinal fluid analysis, amyloid PET imaging ( Ossenkoppele et al, 2015 ) or blood-based measurements ( Chong et al, 2021 ), brain perfusion (e.g. using transcranial Doppler ( Vinciguerra et al, 2019 ) or arterial spin labeling MRI ( van den Brink et al, 2021 ), and brain plasticity and reserve (e.g.…”

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

“…Based on previous studies, extracellular senile plaques composed of deposits of β-amyloid (Aβ) peptide and neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein are widely recognized as pathological hallmarks of AD ( Jack et al, 2013 ; Chong et al, 2021 ). However, despite great expectations, only a small number of antibodies targeting Aβ or tau have been selected for investigation in clinical trials ( Long and Holtzman, 2019 ).…”