Article • Promising, but in need of further validation

Implementation challenges of blood biomarkers for Alzheimer’s disease

Blood-based biomarker (BBB) tests may represent the best weapon to combat the soaring rates of Alzheimer’s disease (AD) throughout the world. Existing clinically validated tests are currently deployed to facilitate diagnosis, to monitor disease and effectiveness of treatments, to quantify progression, and to determine if a patient is appropriate for treatment or participation in a clinical trial.

Report: Cynthia E. Keen

Historically, diagnosis of AD has been based on clinical observations and apparent symptoms, and, for those with access and the funds to pay, lumbar spinal puncture for a cerebrospinal fluid (CSF) test or for a PET imaging scan.

With the proliferation of BBB tests in clinical development, and with increasing levels of accuracy attained, they are expected to become a global tool to fight this most common of dementias. However, there are many challenges to be overcome yet, both with the tests themselves and with their clinical implementation.

Test equipment challenges

The most accurate tests today use mass spectroscopy, which outperform immune-based methods of measuring plasma in accuracy and reliability. Korean researchers from Hanyang University College of Medicine in Seoul conducted an in-depth review of current methodologies used in published research to measure Amyloid-beta (Aβ) plasma. They discovered ‘considerable variance in the diagnostic efficacy of plasma Aβ, contingent upon the measurement techniques employed. Ionization-mass spectroscopy exhibited superior performance, while single molecule array (SIMOA) technology did not yield comparable results,’ wrote lead author Hyuk Sung Kwon, MD, PhD.¹

Mass spectrometry-based assays require specific expertise and infrastructure, are time consuming, and yield lower throughput with immunoassays. The equipment is expensive and not available in many hospital and clinic laboratories.²

However, immune-based methods are currently used for CSF analysis. In addition to immunoassays producing less accurate results of BBB tests they are also subject to batch-to-batch variation, antibody reproducibility, and potential cross-reactivity. They offer automated processing, lower cost, and can deliver rapid turnaround time for point-of-care testing capability. And equipment is in the lab. These factors make a strong case for the development of BBB tests specifically designed for immunoassays.

Article • Detection of neurodegenerative condition

Developing blood biomarkers to diagnose Alzheimer’s disease

There is no known cure for Alzheimer’s disease (AD), although prescription drug-based treatments that can slow AD progression in some patients are starting to enter clinical use. Biomarkers, quantifiable characteristics of biological processes or pathological conditions of the body, are making it possible to help identify and measure the presence and extent of AD and its degenerative…

Standardisation challenges

Another challenge relates to collecting viable samples for processing in remote or low-economy geographic areas with inadequate laboratory infrastructure. Expansion of testing capability of more robust samples, such as dried blood spot, could help resolve such issues.

True standardisation will require the derival and validation of cutoffs that are translatable between methodological approaches for respective blood biomarkers
Michel Schöll, Inge Verberk, Marta del Campo et al.

When multiple tests are available from multiple vendors, the cost of blood biomarker analysis is expected to drop. While this is expected to make BBB testing more accessible throughout the world, standardisation for blood biomarker measurements is imperative. Reproducible, accurate, and consistent results are essential. The Global Biomarker Standardization Consortium of the Alzheimer’s Association has been overseeing this critical issue as well as the development of certified reference material.

Both tasks are enormous in scope and scale, but essential for widespread global adoption.

Prof. Michel Schöll, Ph.D., of the University of Gothenburg and the Wallenberg Centre for Molecular and Translational Medicine, and colleagues, write: ‘Standardisation challenges will vary greatly depending on the blood biomarker and analytic approaches used for its measurement.’ They add, ‘True standardisation will require the derival and validation of cutoffs that are translatable between methodological approaches for respective blood biomarkers.’

Standardisation reference values are made more complex by the fact that the requirements for the diagnostic performance of a biomarker are determined by the BBB test’s context of use. As an example, a test to “rule in” AD needs a higher specificity cut point to minimise false positives, whereas a “rule out” test needs a high sensitivity cut point, to minimize false negatives.³

Challenges of population ethnic diversity, medical comorbidities, and confounding factors

Most BBB tests have been tested and validated in clinical trials with patient cohorts of non-Hispanic Caucasian people, who have few health-related comorbidities, and who live in developed economies in countries north of the Equator. Research is starting to reveal that co-morbidities, such as chronic kidney disease, hypertension, history of cancer and/or cardiac arrest, diabetes, and some prescription drugs, can each impact biomarker concentrations in the blood.

Alzheimer’s BBB research of the diverse ethnic, genetic, cultural and demographic factors, and socioeconomic different populations of Africa, South Asia, Central America and South America has just begun, and is sparse compared to research in Europe, North America, China, Korea and Japan. Yet, approximately 60% of people living with dementia are estimated to be from low-income and middle-income countries in these under-researched areas.⁴

This is a massive and complex challenge. ‘The unavailability of reliable reference intervals for highly diverse populations could lead to the misinterpretation of laboratory test results and contribute to misdiagnosis and inappropriate clinical intervention in a diverse real-world setting with greater heterogeneity among individuals,’ writes Schöll and his multi-national team of co-authors.

Harald Hampel, MD, PhD, Chief Medical Officer and Senior Vice President, Neurology from Japan-based pharmaceutical company Eisai, and co-authors are more blunt: ‘While the performance of BBBs in highly selective populations provides initial information, a broader understanding of how these biomarkers behave within the global community at large is needed to provide clinical guidance. It is imperative to conduct rigorous validation studies in more representative, real-world populations to determine which measures perform most consistently and to establish cutoffs and reference intervals that perform reliably across all patient groups.’

BBB tests in current clinical use are making diagnoses and AD monitoring more precise, and are facilitating AD research through better selection of patient cohorts for clinical trials. Still, it is going to take years before BBB testing can reach the lofty but much needed goal of stemming the epidemic of AD.

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06.03.2025