Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress

Abstract

Biomarkers in Alzheimer's disease (AD) have the potential to allow early and more accurate diagnosis, predict disease progression, stratify individuals and track response to candidate therapies in drug trials. The first fluid biomarkers reflecting aspects of AD neuropathology were identified in cerebrospinal fluid (CSF) in the 1990s. Three CSF biomarkers (amyloid-β 1-42, total tau and phospho-tau) have consistently been shown to have diagnostic utility and are incorporated into the new diagnostic criteria for AD. These markers have also been shown in longitudinal studies to predict conversion of mild cognitive impairment to AD. However, a key issue with the use of CSF biomarkers as a screening test is the invasiveness of lumbar puncture. Over the last 20 years there has been an active quest for blood biomarkers, which could be easily acquired and tested repeatedly throughout the disease course. One approach to identifying such markers is to attempt to measure candidates that have already been identified in CSF. Until recently, this approach has been limited by assay sensitivity, but newer platforms now allow single molecule-level detection. Another approach is identification of candidates in large multiplex panels that allow for multiple analytes to be quantified in parallel. While both approaches show promise, to date no blood-based biomarker or combination of biomarkers has sufficient predictive value to have utility in clinical practice. In this review, an overview of promising blood protein candidates is provided, and the challenges of validating and converting these into practicable tests are discussed. AQ1H. Zetterberg and J. M. Schott are joint senior author of this article. Key PointsMany studies have identified candidates for blood biomarkers of Alzheimer's disease (AD) but replication has been problematic.The two main candidates showing promise currently are plasma total tau and serum neurofilament light chain.New techniques such as multiplexing and use of more sensitive assays are likely to expand and improve blood biomarker research.

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“…While this study refutes the superficial ‘nothing replicates’ dismissal, it remains the case that in the field as a whole, most nominated biomarkers fail replication posing a substantial challenge to development [ 60 ]. The reason for such failure might be caused by the heterogeneity of the disease itself as well as the complexity of blood.…”

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“…Therefore, the search for appropriate biomarkers from other fluids such as blood or urine still continues. 16 Particularly, other specific AD biomarkers, often based on multiplexed approaches and proteomic studies 17 have been explored and proposed, take into account the multifaceted nature of this disease. For example, although blood measures of tau and neurofilament light chain 18 are currently considered as possible blood-based biomarker candidates, further work is required to understand what role they might play in the diagnosis of AD.…”

“…Moreover, the diagnostic use of CSF is limited because the use of lumbar puncture is invasive and varies between countries. Therefore, the search for appropriate biomarkers from other fluids such as blood or urine still continues . Particularly, other specific AD biomarkers, often based on multiplexed approaches and proteomic studies have been explored and proposed, take into account the multifaceted nature of this disease.…”

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“…HLA proteins used by the immune system to recognize “self” are used to match patients and donors for bone marrow transplants . Researchers also discovered a panel of protein biomarkers that may detect Alzheimer's disease . Metabolites are an additional class of important biomarkers that reflect not only what has been encoded by the genome, but also inputs from the environment including diet and microbiome.…”

“…[64] Researchers also discovered a panel of protein biomarkers that may detect Alzheimer's disease. [65] Metabolites are an additional class of important biomarkers that reflect not only what has been encoded by the genome, but also inputs from the environment including diet and microbiome. Metabolites are often the closest representation of phenotype.…”