Blood-based molecular biomarkers for Alzheimer’s disease

Abstract

A major barrier to the effective conduct of clinical trials of new drug candidates against Alzheimer's disease (AD) and to identifying patients for receiving future disease-modifying treatments is the limited capacity of the current health system to find and diagnose patients with early AD pathology. This may be related in part to the limited capacity of the current health systems to select those people likely to have AD pathology in order to confirm the diagnosis with available cerebrospinal fluid and imaging biomarkers at memory clinics. In the current narrative review, we summarize the literature on candidate blood tests for AD that could be implemented in primary care settings and used for the effective identification of individuals at increased risk of AD pathology, who could be referred for potential inclusion in clinical trials or future approved treatments following additional testing. We give an updated account of blood-based candidate biomarkers and biomarker panels for AD-related brain changes. Our analysis centres on biomarker candidates that have been replicated in more than one study and discusses the need of further studies to achieve the goal of a primary care-based screening algorithm for AD.

Prediction of Alzheimer's disease diagnosis within 14 years through Aβ misfolding in blood plasma compared to APOE4 status, and other risk factors

“…Recently, several AD blood biomarkers have been developed and validated, which determine A pathology in the brain. 14,15,34,35 In a study by Nakamura et al, 16 a blood-based A biomarker showed high accuracy in predicting brain amyloid-burden; however, it should be taken into account that these results are compared only to PET imaging (AUC discovery = 0.97 and AUC validation = 0.94) and not clinical diagnosis as in this study. It is to be expected that blood biomarkers will also be tested longitudinally in large epidemiologic cohorts to assess their potential as risk factors in clinical settings and in the general population.…”

“…Recently, several AD blood biomarkers have been developed and validated, which determine Aβ pathology in the brain . In a study by Nakamura et al., a blood‐based Aβ biomarker showed high accuracy in predicting brain amyloid‐β burden; however, it should be taken into account that these results are compared only to PET imaging (AUC discovery = 0.97 and AUC validation = 0.94) and not clinical diagnosis as in this study.…”

“…Cerebrospinal fluid (CSF)‐derived or positron emission tomography (PET) imaging biomarkers express physiological changes associated with disease pathology but are invasive or cost‐prohibitive . Emerging Aβ‐targeted blood‐based biomarkers or risk stratification strategies could present a promising alternative for early identification of AD pathological changes while being minimally invasive and cost‐effective …”

“…Aβ is known to undergo a structural change from monomeric, alpha‐helical, or disordered conformations to β‐sheet‐enriched isoforms during disease progression and these β‐sheet‐enriched isoforms are the basis of plaque formation in the brain. It has been shown that Aβ misfolding not only is observable in the brain but also correlates to Aβ misfolding in CSF and plasma . The focus of previous Aβ‐targeted plasma studies has largely been on validation of a biomarker comparing patients with clinically manifest AD and healthy controls in a clinical setting .…”

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course—a joint PhD student course at University College London and University of Gothenburg

“…However, concentration of CNS biomarkers outside of CSF is often extremely low, making it difficult to detect using standard assays. Other important factors complicating the analysis include peripheral expression of the protein of interest, endogenous antibodies interfering with assay results and presence of proteases which shorten the lifespan of the protein in peripheral tissues [96].…”