Plasma biomarkers for neurodegenerative disorders: ready for prime time?

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Purpose of review

Several plasma biomarkers for Alzheimer's disease and related disorders (ADRD) have demonstrated clinical and technical robustness. However, are they ready for clinical implementation? This review critically appraises current evidence for and against the immediate use of plasma biomarkers in clinical care.

Recent findings

Plasma biomarkers have significantly improved our understanding of ADRD time-course, risk factors, diagnosis and prognosis. These advances are accelerating the development and in-human testing of therapeutic candidates, and the selection of individuals with subtle biological evidence of disease who fit the criteria for early therapeutic targeting. However, standardized tests and well validated cut-off values are lacking. Moreover, some assays (e.g., plasma Aβ methods) have poor robustness to withstand inevitable day-to-day technical variations. Additionally, recent reports suggest that common comorbidities of aging (e.g., kidney disease, diabetes, hypertension) can erroneously affect plasma biomarker levels, clinical utility and generalizability. Furthermore, it is unclear if health disparities can explain reported racial/ethnic differences in biomarker levels and functions. Finally, current clinically approved plasma methods are more expensive than CSF assays, questioning their cost effectiveness.

Summary

Plasma biomarkers have biological and clinical capacity to detect ADRD. However, their widespread use requires issues around thresholds, comorbidities and diverse populations to be addressed.

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Most cited references 71

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NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Clifford R. Jack, David Bennett, Kaj Blennow … (2018)

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Akinori Nakamura, NAOKI KANEKO, Victor Villemagne … (2018)

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

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Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts

Thomas Karikari, Tharick A. Pascoal, Nicholas J. Ashton … (2020)

CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.

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Author and article information

Journal

Journal ID (nlm-ta): Curr Opin Psychiatry

Journal ID (iso-abbrev): Curr Opin Psychiatry

Journal ID (publisher-id): COIP

Title: Current Opinion in Psychiatry

Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )

ISSN (Print): 0951-7367

ISSN (Electronic): 1473-6578

Publication date (Print): March 2023

Publication date (Electronic): 16 January 2023

Volume: 36

Issue: 2

Pages: 112-118

Affiliations

[a ]Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

[b ]Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg

[c ]Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

[d ]Department of Neurodegenerative Disease, UCL Institute of Neurology

[e ]UK Dementia Research Institute at UCL, London, UK

[f ]Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

[g ]Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin

[h ]Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

Author notes

Correspondence to Thomas K. Karikari, PhD, Assistant Professor, Clinical Neurochemistry Lab., Sahlgrenska University Hospital, House V3/SU, 43 180 Mölndal, Sweden. E-mail: Thomas.Karikari@ 123456gu.se and Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara Street, 15213, Pittsburgh, PA, USA. E-mail: Karikari@ 123456pitt.edu

Article

Publisher ID: YCO360207 Accession ID: 00005

DOI: 10.1097/YCO.0000000000000851

PMC ID: 9872855

PubMed ID: 36607770

SO-VID: 3af51952-d027-4a97-aa35-285acbabee43

License:

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

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Keywords: alzheimer's disease,alzheimer's disease and related disorders,dementia,neurodegenerative disorder,plasma biomarker

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Keywords: alzheimer's disease, alzheimer's disease and related disorders, dementia, neurodegenerative disorder, plasma biomarker

Plasma biomarkers for neurodegenerative disorders: ready for prime time?

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Purpose of review

Recent findings

Summary

Related collections

UCL: UN SDG 10 Reduced Inequalities

Most cited references 71

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

High performance plasma amyloid-β biomarkers for Alzheimer’s disease

Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts

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