Jul 2026· Expert Review of Neurotherapeutics· Vol 26, pp. 839 - 852· 0 citations· 128 references
Medicine
TL;DR
The authors critically appraise the current evidence supporting plasma phosphorylated tau at threonine 217 (p-tau217) as the leading BBM for AD, and highlight current limitations, unresolved challenges, and future perspectives for the integration of plasma biomarkers into routine clinical practice.
Abstract
ABSTRACT Introduction Alzheimer’s disease (AD) is a clinical-biological entity in which pathophysiological changes precede symptoms by years. Biomarkers are essential for early and accurate diagnosis, particularly in the era of disease-modifying therapies requiring biological confirmation. Cerebrospinal fluid (CSF) and amyloid positron emission tomography (amyloid-PET) are the reference standards, but increasing attention is devoted to blood-based biomarkers (BBMs) due to their scalability and cost-effectiveness. Areas covered In this critical perspective, the authors critically appraise the current evidence supporting plasma phosphorylated tau at threonine 217 (p-tau217) as the leading BBM for AD. They also discuss its analytical performance, biological rationale, and diagnostic accuracy across the AD continuum, its relationship with established CSF, PET, and neuropathological biomarkers, its potential role in identifying patients eligible for disease-modifying therapies, and the main clinical and biological factors influencing its interpretation. Finally, they highlight current limitations, unresolved challenges, and give their future perspectives for the integration of plasma biomarkers into routine clinical practice. Expert opinion BBMs are expected to reshape AD diagnostics. A stepwise approach, using plasma biomarkers as first-line tests followed by confirmatory CSF or PET, is currently the most feasible strategy. Ultimately, highly specific, brain-derived tau biomarkers may enable BBMs to replace CSF biomarkers.
Blood-based biomarkers (BBMs) are increasingly being integrated into Alzheimer’s disease (AD) clinical pathways by providing scalable tools to track amyloid, tau, neurodegeneration, and inflammation dimensions of the ATN-I framework. As biological characterization and biomarker-informed assessment are increasingly integrated into AD care, there is growing interest in clinically applicable blood-based approaches capable of reflecting AD-related biological changes across different disease stages. This review examines recent advances in BBMs through the ATN-I framework while emphasizing their clinical decision value, analytical feasibility, economic considerations, and implementation barriers across different healthcare settings. Building on these findings, we examine the evidence supporting clinical use, with a focus on appropriate use criteria, clinical validation, laboratory feasibility, and consistent interpretation methods. Furthermore, this review explores how integrating BBMs with traditional cerebrospinal fluid and neuroimaging tests may support symptom-driven clinical triage, probability refinement, and early evaluation in selected individuals, improving clinical workflow efficiency and accessibility. Finally, the article addresses remaining challenges related to clinical validation, platform accessibility, cost-effectiveness, and equitable deployment, highlighting how emerging biomarker strategies may contribute to more scalable AD assessment.
B. Xie, Wang Zhang, Yu Zhang et al.· Frontiers in Aging Neuroscie...· 0 citations
Plasma biomarkers offer a transformative, non-invasive approach to early AD diagnosis and primary care triage, reducing reliance on CSF and PET scans and overcoming demographic and methodological limitations is essential for their widespread clinical adoption.
Małgorzata Witaszczyk, Alicja Sołtan, Natalia Wiktorzak et al.· International Journal of Inn...· 0 citations
The introduction of blood-based biomarkers (BBMs) for Alzheimer’s disease (AD) represents one of the most transformative advances in neurodegenerative disease research over the past decade. 1,2 For the first time, biological evidence of AD pathology can be obtained through a minimally invasive, scalable blood test, opening new opportunities for early diagnosis, patient triage, and implementation of disease-modifying therapies. 3 Among the available biomarkers, phosphorylated tau (p-tau) species, particularly plasma p-tau217, have consistently shown excellent diagnostic performance across the AD continuum, recently culminating in regulatory approval of plasma p-tau217-based assays in both the USA and Europe. 4–6 Despite this remarkable clinical success, a fundamental paradox remains. Plasma tau biomarkers work
Lucilla Parnetti, L. Gaetani· EBioMedicine· 0 citations
Background. Alzheimer's disease (AD) accounts for 60–70% of the over 57 million dementia cases worldwide and is projected to nearly triple by 2050. Neuropathology precedes symptoms by roughly two decades, and the approval of anti-amyloid therapies has made biomarker-confirmed early diagnosis a clinical priority.
Aim. This narrative review synthesizes evidence on cerebrospinal fluid (CSF), blood, neuroimaging, genetic, retinal, and emerging molecular biomarkers for early detection of AD, framed within the 2024 revised NIA-AA biological criteria.
Material and methods. PubMed, MEDLINE, Google Scholar, the Journal of Education, Health and Sport, and Quality in Sport were searched for studies and consensus documents published between 2014 and 2026. Six mandatory references were integrated with seventeen additional peer-reviewed sources.
Results. CSF Aβ42/40, total tau, and p-tau181 remain reference-standard markers. Plasma p-tau217 has emerged as the leading minimally invasive biomarker, with areas under the curve of 0.92–0.96 against amyloid PET. Serum neurofilament light and glial fibrillary acidic protein support staging and differential diagnosis. Amyloid and tau PET enable in vivo Braak staging; structural MRI tracks hippocampal atrophy. APOE ε4 genotyping has regained clinical relevance in the anti-amyloid era. Optical coherence tomography, metabolomics, microRNAs, and AI-driven multimodal models expand the diagnostic frontier.
Conclusions. AD can now be detected biologically before symptoms become disabling. Translating plasma assays and AI-supported imaging into routine practice is the central challenge of the coming decade.
Aleksandra Rucka, Mateusz Kowalski, Michał Rucki et al.· Journal of Education, Health...· 0 citations
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
Over the past years, there has been an evident change in the perspective of the Alzheimer disease field where descriptive clinical diagnosis has been replaced by a biological one where molecular marker that indicate amyloid deposition, tau protein phosphorylation abnormalities, and the degree of neuron and glial damage are measured. Aβ42, Aβ40, and the Aβ42/Aβ40 ratio, as well as total tau, p-tau181, p-tau217, p-tau231, neurofilament light chain (NfL) and GFAP, the most established neurobiological markers in this area, as they connect the disease on the one hand, and the possibility of early detection, biomarker classification, and longitudinal follow-up on the other. The purpose of the review is to put these markers in a practical context based on the nature of the biological sample and the laboratory platforms to measure them, the distinctions between conventional and automated immunoassays, ultra-sensitive Simoa methods, and LC-MS/MS mass spectrometry, and to discuss the strengths and weaknesses of each method. The review also covers issues of pre-analysis, analytical validation, compatibility with the platform and derivation of cutoff values, and then considers future trends that lead to more clinically useful blood tests, such as automated tests and those that have recently undergone sophisticated regulatory review. The review finds that the real worth of these biomarkers is not just in their availability but also in choosing the right biomarker to the right clinical question and in maintaining the integrity of the measurement chain between sample collection and interpreting the results.
Mustafa Alburhan, Abdulla Munthir Sulaiman, Bakr Aldoori· Libyan Journal of Applied an...· 0 citations
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