Blood-based testing for Alzheimer’s disease has moved quickly from research use toward clinical adoption. In 2025, Fujirebio’s Lumipulse® G pTau 217/β-Amyloid 1-42 Plasma Ratio became the first FDA-cleared blood-based IVD test to aid in identifying amyloid pathology associated with Alzheimer’s disease in adults 50 and older being evaluated in a specialized care setting, and Roche’s Elecsys® pTau181 was cleared to help rule out Alzheimer’s-related amyloid pathology in symptomatic adults 55 and older. In 2026, a second Roche clearance followed for Elecsys pTau217, covering rule-in and rule-out assessment of amyloid pathology in individuals 55 and older with signs, symptoms, or complaints of cognitive decline, and C2N Diagnostics’ PrecivityAD2™ was cleared to aid evaluation of symptomatic adults 40 and older. These milestones show how quickly blood-based biomarkers are becoming part of the clinical conversation, and why sample quality will matter as testing expands beyond highly controlled settings.
The shift is familiar from liquid biopsy. Circulating tumor DNA (ctDNA) and plasma protein assays show that a blood draw can support less invasive testing, but only when the sample is managed carefully between collection and analysis. Neurodegeneration research now faces a similar challenge as blood-based biomarkers move into larger studies and broader clinical use.
From CSF to Blood
For much of Alzheimer’s biomarker research, cerebrospinal fluid (CSF) has been an important reference sample type because amyloid-beta and tau concentrations can reflect central nervous system biology. However, lumbar puncture is invasive, requires trained personnel, and is not practical for repeated sampling, decentralized studies, community screening efforts, or large biobanks.
Blood improves access. A venous draw can be performed in primary care offices, mobile collection sites, and participant homes. But broader access also introduces variability: samples may spend more time in transit, experience different temperatures, or wait longer before processing. In that environment, analytical performance depends not only on the assay, but also on whether the collection workflow protects the sample before it reaches the lab. These are the kinds of pre-analytical variables that liquid biopsy workflows have had to address and that neurodegeneration studies now need to manage.
Scaling Neuro Biomarkers
Current use still requires precision. Cleared plasma tests are intended for people with signs or symptoms of cognitive impairment, not for population screening, and results should be interpreted alongside other clinical information. A 2025 clinical practice guideline has emphasized this symptomatic-evaluation context (Palmqvist et al., 2025).
At the same time, prevention studies, longitudinal cohorts, and biobanks point toward broader collection networks. As sampling expands beyond academic memory clinics, collection conditions become less uniform and the time between draw and processing becomes an operational variable. That is where sample handling begins to matter at scale.
Lessons from Liquid Biopsy
Oncology has already worked through many of these challenges. Multicenter ctDNA trials, biobank collections, and decentralized cancer screening studies rely on defined collection tubes, transport conditions, and processing windows so results can be compared across sites. Those controls helped make blood-based testing more reproducible as oncology workflows moved from specialized research protocols toward broader clinical and commercial use. For example, degradation of cell-free DNA or release of genomic DNA from lysed leukocytes can distort plasma DNA measurements, creating variability that may go unnoticed unless these risks are specifically evaluated and controlled. Blood-based neurodegeneration biomarkers can face comparable risks, even when the analytes are proteins rather than nucleic acids. Some markers may degrade or bind to surfaces before processing. Others may be present at higher concentrations inside blood cells or platelets than in plasma, so cell lysis or platelet activation can alter the measured signal. For assay developers moving neuro panels into multisite studies, standardized collection and handling conditions are part of generating comparable data.
The Next Wave of Neurodegeneration Research
Alzheimer’s disease is furthest along, but neurodegeneration research is expanding into additional biomarkers and disease areas. Panels may include alpha-synuclein for Parkinson’s disease and other synucleinopathies, TDP-43 for amyotrophic lateral sclerosis (ALS) and related proteinopathies, neurofilament light chain (NfL) for axonal injury, and GFAP for astrocytic activation. As panels become more complex, one blood sample may need to preserve analytes with different stability profiles, making sample quality an early study-design consideration.
The next wave may also extend beyond soluble proteins. Blood-based studies are increasingly evaluating extracellular vesicles and their molecular cargo, including RNA species such as microRNAs, because these vesicles may carry signatures from specific cell types, including cells of the central nervous system (Park et al., 2024). That opportunity also adds complexity: extracellular vesicle measurements can be affected by how samples are collected, processed, stored, and isolated, making standardization especially important as these approaches move from discovery toward larger studies.
These emerging markers are unlikely to replace amyloid and tau measures on their own. Their value may be in adding biological context. A multimarker approach could help researchers distinguish amyloid pathology from broader neurodegenerative injury, astrocyte activation, synucleinopathy, TDP-43 proteinopathy, or cell-derived molecular changes captured in extracellular vesicles. As the field moves in this direction, sample quality becomes even more important because each analyte may respond differently to collection, processing, storage, and cellular carryover.
Why Sample Quality Matters
Pre-analytical studies show why those details matter. The same collection and processing conditions may affect biomarkers differently, which is why each analyte needs to be evaluated in the context of its biology and intended workflow. In a 2025 consensus study, collection tube type affected every Alzheimer’s blood biomarker tested by more than 10 percent (Verberk et al., 2025). Amyloid-beta peptides were most sensitive to storage and centrifugation delays, while phosphorylated tau isoforms were more resistant to delay, temperature, and freeze-thaw cycling. A separate p-tau217 study also found that up to three freeze-thaw cycles did not significantly affect assay performance (Bali et al., 2024).
The amyloid beta 42/40 ratio is more sensitive to handling. Because amyloid-positive and amyloid-negative individuals may differ by a narrow margin, small pre-analytical or measurement shifts can affect classification. Modeling studies have shown that error in amyloid beta 42 or 40 can contribute to misclassification for this reason (Rabe et al., 2023).
Alpha-synuclein highlights a different risk. More than 99 percent of alpha-synuclein in whole blood is found inside red blood cells, with little normally present in plasma (Barbour et al., 2008). If red blood cells lyse during or after collection, alpha-synuclein can be released into plasma and artificially increase the measured concentration. For panels that include alpha-synuclein, maintaining cell stability through collection, transport, and processing is central to protecting plasma sample quality.
Amyotrophic lateral sclerosis (ALS) and other TDP-43 proteinopathies add another pre-analytical consideration. Although TDP-43 is strongly associated with ALS pathology, its measurement as a plasma biomarker is still emerging. Recent work found that at least 95 percent of TDP-43 in platelet-containing plasma was compartmentalized within platelet cytosol, and that variable platelet recovery in archived plasma may contribute to heterogeneous TDP-43 results (Luthi-Carter et al., 2024). For TDP-43 assays, platelet activation or carryover could change the platelet-derived contribution to the plasma signal, making platelet-control strategies important in study design.
Looking Ahead
Current Alzheimer’s blood testing should not be described as population screening. But as collection models broaden and panels combine analytes with different pre-analytical requirements, neurodegeneration research will need the same attention to workflow standardization that oncology-based liquid biopsy required as it scaled.
For teams designing neuro biomarker studies — whether for a biobank, multisite trial, or decentralized collection model — pre-analytical planning should be part of the protocol from the beginning. Collection tube selection, transport conditions, processing windows, and cell stability can all influence whether assay performance holds up outside a single controlled site. Planning for those variables early can support more consistent data, clearer assay interpretation, and greater confidence when results are compared across sites. Streck’s work in blood collection and sample stabilization has long focused on these types of challenges, and the same questions are worth addressing early as neurodegeneration research continues to scale.
Reading List
Verberk IMW, et al. Evidence-based standardized sample handling protocol for accurate blood-based Alzheimer’s disease biomarker measurement. Alzheimer’s & Dementia. 2025;21:e70752. The consensus standardization study: every biomarker tested varied more than 10% by collection tube; phosphorylated tau was highly resistant, amyloid beta 42/40 most sensitive to storage and centrifugation delay.
Rabe C, Bittner T, Jethwa A, et al. Clinical performance and robustness evaluation of plasma amyloid-β42/40 prescreening. Alzheimer’s & Dementia. 2023;19(4):1393-1402. PMID 36150024. Models how small pre-analytical or measurement errors in amyloid beta 42/40 can cause misclassification, because the ratio’s dynamic range between amyloid-positive and -negative results is narrow.
Bali D, Hansson O, Janelidze S, et al. Effects of certain pre-analytical factors on the performance of plasma phospho-tau217. Alzheimer’s Research & Therapy. 2024;16:31. Source for the tau robustness concession: up to three freeze-thaw cycles had no significant effect on plasma p-tau217 performance.
Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease. Alzheimer’s & Dementia. 2022;18:2669-2686. Establishes the appropriate-use framework blood-based biomarkers have operated under prior to the 2025 clinical practice guideline; specialty-care, symptomatic-evaluation context.
Palmqvist S, Whitson HE, et al. Alzheimer’s Association Clinical Practice Guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer’s disease within specialized care settings. Alzheimer’s & Dementia. 2025;21(7):e70535. DOI 10.1002/alz.70535. The 2025 clinical practice guideline that formally supersedes the Hansson et al. 2022 appropriate-use recommendations; establishes performance-based, brand-agnostic recommendations for blood-based biomarker use in specialized care settings.
Barbour R, Kling K, Anderson JP, et al. Red blood cells are the major source of alpha-synuclein in blood. Neurodegenerative Diseases. 2008;5(2):55-59. PMID 18182779. More than 99% of alpha-synuclein in whole blood resides in red blood cells; the basis for the hemolysis/cell-stability point in the alpha-synuclein discussion.
Luthi-Carter R, Cappelli S, Le Roux-Bourdieu M, et al. Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols. Scientific Reports. 2024;14:21837. DOI 10.1038/s41598-024-70822-8. Source for the ALS/TDP-43 discussion: archived plasma samples showed heterogeneous TDP-43 levels attributed to variable platelet recovery, and fractionation of fresh blood showed that at least 95% of TDP-43 in platelet-containing plasma was compartmentalized within platelet cytosol.
Park C, Weerakkody JS, Schneider R, Miao S, Pitt D. CNS cell-derived exosome signatures as blood-based biomarkers of neurodegenerative diseases. Frontiers in Neuroscience. 2024;18. DOI 10.3389/fnins.2024.1426700. Source for the extracellular vesicle/RNA discussion: circulating CNS cell-derived exosomes can carry protein and RNA cargo that may reflect disease-associated changes, but the field needs more standardized methods for isolation, characterization, and quantification before broad clinical translation.
