The research team, led by Andrea Mastrangelo, Simone Baiardi and Piero Parchi at the University of Bologna and the Institute of Neurological Sciences of Bologna, exploited a rare and powerful resource. Their cohort consisted of participants whose cerebrospinal fluid or plasma samples had been collected shortly before death, with a median sampling-to-death interval of just 1.5 months for cerebrospinal fluid and one month for plasma. This proximity matters enormously. Most neuropathological validation studies suffer from long gaps between the fluid measurement and the autopsy, during which the underlying disease may have progressed substantially, blurring the relationship between what the biomarker showed and what the brain actually contained. By anchoring the measurements to the final weeks of life, the Italian team effectively froze the correspondence between fluid chemistry and brain pathology.

The cohort included 230 participants with antemortem cerebrospinal fluid and 101 with plasma samples, the majority affected by prion disease, a group whose rapidly progressive syndromes prompt autopsy through the Italian surveillance program. The researchers measured five cerebrospinal fluid markers, namely the Aβ42/Aβ40 ratio, p-tau181, p-tau217, and the hybrid ratios Aβ42/p-tau181 and Aβ42/p-tau217, together with three plasma markers, p-tau217, p-tau217/Aβ42 and Aβ42/Aβ40. All assays were run on a single automated chemiluminescent platform, ensuring analytical consistency. Because prion disease itself can elevate tau biomarkers, analyses involving phosphorylated tau were restricted to the 88 participants with non-prion conditions.

On the pathology side, the team went beyond conventional categorical staging. In addition to Thal amyloid phases, Braak neurofibrillary stages and ABC scores of Alzheimer’s neuropathologic change, two blinded evaluators scored amyloid plaques and cerebral amyloid angiopathy across nine brain regions, from neocortex to cerebellum, yielding a cumulative amyloid score from 0 to 90. Tau pathology, including neuropil threads, neurofibrillary tangles and thick neurites, was graded across six cortical regions to produce a cumulative score from 0 to 54. This continuous, region-weighted approach captures the actual regional burden of disease in a way that categorical stages cannot, allowing the researchers to ask precisely how much pathology is required before each biomarker begins to move.

The results reveal a strikingly sequential pattern. The cerebrospinal fluid Aβ42/Aβ40 ratio was the earliest mover, declining significantly already at the second quartile of amyloid burden, corresponding to mild-to-moderate plaque deposition across neocortical and limbic regions, and falling progressively further in the third and fourth quartiles. By contrast, cerebrospinal fluid p-tau181 and p-tau217 rose significantly only from the third quartile of amyloid burden, indicating that tau phosphorylation in the fluid lags behind the initial phases of plaque accumulation. The hybrid ratios behaved like early amyloid markers in terms of onset, with Aβ42/p-tau217 decreasing significantly from the second amyloid quartile, yet their abnormalities in relation to standard staging emerged only at intermediate levels of Alzheimer’s neuropathologic change, unlike the Aβ42/Aβ40 ratio, which was already reduced at low levels.

Sequential receiver operating characteristic analyses sharpened this picture by testing how well each biomarker discriminated progressively higher pathology thresholds. The cerebrospinal fluid Aβ42/Aβ40 ratio achieved its peak accuracy at low-to-intermediate amyloid burden, with an area under the curve of 0.984 at a threshold above 16 in the non-prion subgroup, before showing a modest plateau at more advanced stages. The p-tau markers and their ratios performed best at higher amyloid thresholds, with areas under the curve ranging from 0.889 to 0.980, and at intermediate tau burden, where p-tau217 and Aβ42/p-tau217 reached extraordinary values of 0.994 and 0.995 respectively at a tau score above 15. Across both amyloid and tau continua, p-tau217 consistently outperformed its p-tau181 counterpart, reinforcing a growing consensus that phosphorylation at threonine 217 is the more informative tau epitope.

The plasma results told a more sobering story. Plasma p-tau217 and p-tau217/Aβ42 rose significantly only in the highest quartiles of both amyloid and tau burden, and their discriminatory power peaked at the most advanced thresholds, with areas under the curve between 0.893 and 0.928. Plasma Aβ42/Aβ40 showed only weak associations with pathology and poor discrimination across the entire amyloid continuum, a finding the authors attribute to possible peripheral contributions to circulating amyloid peptides, systemic confounders and blood-brain barrier effects. When both pathologies were modeled simultaneously, plasma p-tau217 remained independently associated only with tau burden, consistent with evidence that a marked surge in soluble p-tau217 release accompanies the spread of tau pathology into the neocortex.

These findings carry practical weight for the clinic and for drug development. The team showed that a cerebrospinal fluid Aβ42/Aβ40 cut-off below 0.074, slightly higher than values commonly used in clinical practice, achieved 95 percent specificity for identifying subjects with at least low Alzheimer’s neuropathologic change, supporting its use for early identification within the disease continuum. The staged behavior of the markers also aligns with therapeutic evidence suggesting that anti-amyloid antibodies such as donanemab and lecanemab exert greater clinical benefit at earlier pathological stages, and that plaque clearance proceeds faster in brains with lower amyloid load. Knowing which fluid marker corresponds to which pathological window could therefore help clinicians time interventions and interpret biomarker panels more rationally.

Equally important is what the study could not find. Even the best-performing cerebrospinal fluid marker, the Aβ42/Aβ40 ratio, showed limited accuracy at the very earliest phases of plaque formation, when only sparse neocortical deposits are present. This implies an initial window in the Alzheimer’s continuum that current fluid biomarkers do not fully capture, a gap that may matter for prevention trials aiming to intervene before substantial pathology accumulates. The authors also caution that their cohort, enriched for rapidly progressive syndromes and dominated by participants with no or low Alzheimer’s neuropathologic change, may limit generalizability, that kidney function data were largely unavailable, and that reliance on a single assay platform precludes direct comparison with other technologies.

Nevertheless, the study delivers a coherent and clinically actionable model of biomarker behavior across the Alzheimer’s pathological continuum. Cerebrospinal fluid Aβ42/Aβ40 emerges as the sentinel of early amyloid deposition, cerebrospinal fluid p-tau markers and hybrid ratios as indicators of advancing combined pathology, and plasma p-tau217 measures as signals of heavy, late-stage burden. As blood-based testing moves toward primary care and anti-amyloid therapies become routine, anchoring these tests to neuropathological ground truth, with sampling intervals measured in weeks rather than years, provides the kind of validation the field has long needed. The sequential model also sets a clear benchmark for the next generation of markers, which must reach further back into the disease process if the earliest, most treatable phases of Alzheimer’s pathology are to be caught in a tube of fluid.

Subject of Research: Neuropathological validation of cerebrospinal fluid and plasma Alzheimer's disease biomarkers across increasing brain amyloid-beta and tau pathology burden

Article Title: Changes in five cerebrospinal fluid and three plasma Alzheimer’s disease biomarkers across increasing brain amyloid-beta and tau pathology burden

Article References: Mastrangelo, A., Baiardi, S., Ruggeri, E., Bentivenga, G. M., Vargiu, C. M., Mammana, A., Sbriccoli, M., Polischi, B., Carlà, B., Capellari, S., & Parchi, P. (2026). Changes in five cerebrospinal fluid and three plasma Alzheimer’s disease biomarkers across increasing brain amyloid-beta and tau pathology burden. Acta Neuropathologica, 152(1), Article 28. https://doi.org/10.1007/s00401-026-03076-5

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03076-5

Keywords: Alzheimer's disease, biomarkers, amyloid-beta, tau pathology, cerebrospinal fluid, plasma p-tau217, neuropathology, autopsy validation, Aβ42/Aβ40 ratio, p-tau181, diagnostic accuracy, neurodegeneration

For decades, the diagnosis of Alzheimer’s has been a challenging endeavor, particularly because the symptoms, such as cognitive decline and memory impairment, can stem from various causes. Existing blood tests have primarily focused on detecting the presence of Alzheimer’s-related proteins, such as amyloid beta, which accumulates in plaques in the brain. However, the key innovation from this research lies in its ability to measure the levels of a specific tau protein, known as MTBR-tau243. The ability to determine how far Alzheimer’s disease has progressed using this biomarker could profoundly influence treatment decisions.

The study reveals that MTBR-tau243 levels in the bloodstream hold a direct correlation with the accumulation of toxic tau aggregates in the brain, providing a clear picture not only of whether an individual has Alzheimer’s but also of the disease’s stage. This relationship is vital since current Alzheimer’s therapies prove most effective at the early stages of the disease. Understanding a patient’s degree of impairment is essential for physicians to tailor treatments accordingly, ensuring that individuals receive the most appropriate therapeutic options based on their specific needs.

Additionally, the researchers highlighted that elevated blood levels of MTBR-tau243 distinguished between individuals with mild cognitive impairment due to Alzheimer’s disease and those experiencing full-blown dementia, thus confirming its utility as both a diagnostic and a staging tool. Unlike previously available blood tests, which were primarily diagnostic, this novel test could also serve as a prognostic tool, opening avenues for personalized treatment strategies.

The technology and methodologies used in this study evolved from work that has been in progress for several years, wherein researchers have investigated the linking of tau levels in cerebrospinal fluid to tau tangles in the brain. Building on this foundation, the research team succeeded in developing techniques to analyze tau levels in peripheral blood, a major advancement considering that blood samples are significantly easier and less invasive to collect than cerebrospinal fluid, which requires a spinal tap.

In their investigation, the team tested blood samples from various cohorts, initially focusing on individuals with cognitive decline. This included 108 volunteers from WashU’s Charles F. and Joanne Knight Alzheimer Disease Research Center and 55 participants from the Swedish BioFINDER-2 cohort. Utilizing an independent dataset of 739 additional individuals helped further validate their findings.

The analysis concluded that the blood concentration of MTBR-tau243 could accurately reflect the density of tau tangles in the brain, achieving an impressive accuracy rate of 92%. Remarkably, this biomarker remained stable in cognitively healthy participants, indicating that MTBR-tau243 levels do not fluctuate until Alzheimer’s symptoms are present. Conversely, among those suffering from cognitive impairments attributed to Alzheimer’s, the protein levels exhibited significant elevation, providing a clear differentiation from individuals with cognitive issues stemming from other conditions.

Importantly, the implications of these findings extend beyond immediate diagnostics and staging. They could revolutionize the treatment landscape for Alzheimer’s disease by integrating an array of therapeutic options that are reflective of the disease state. As researchers work tirelessly on developing novel tau-targeting medications, the MTBR-tau243 blood test could play an integral role in identifying the best therapeutic approaches suited for each stage of the disease.

Personalized treatment regimens are also on the horizon, supported by this significant development in blood testing technology. With the FDA approving therapies targeting amyloid beta, ongoing research suggests that upcoming treatments may include those focusing on tau pathology. Once a standardized blood test for Alzheimer’s staging becomes available, healthcare providers will be empowered to devise tailored treatment plans aimed at addressing patients’ unique disease trajectories effectively.

As reported by Randall J. Bateman, MD, co-senior author of the study, the ability to more readily identify distinct aspects of Alzheimer’s pathology and apply this knowledge to clinical practice may greatly enhance patient care. The promise of SAT tests, such as those measuring MTBR-tau243, not only simplifies the complexities of diagnosis but could also refine the strategies employed by medical professionals treating Alzheimer’s disease.

In summary, the emergence of the MTBR-tau243 blood test represents a quintessential move towards a more accessible and accurate diagnostic and prognostic framework for Alzheimer’s disease. Continuous innovations within this realm promise not only to illuminate our understanding of Alzheimer’s pathology but also pave the way for enhanced personalized approaches to treatment, fundamentally shifting the future of care for patients experiencing this challenging neurodegenerative disorder.

Subject of Research: Alzheimer’s disease detection through blood testing
Article Title: Plasma MTBR-tau243 Identifies Tau Tangle Pathology in Alzheimer’s Disease
News Publication Date: March 31, 2025
Web References: Nature Medicine
References: Horie K, Salvadó G, etc. (2025). Plasma MTBR-tau243 identifies tau tangle pathology in Alzheimer’s disease. Nature Medicine.
Image Credits: Matt Miller

Keywords: Alzheimer’s disease, neurodegenerative disorders, blood biomarkers, tau proteins, medical diagnostics, personalized medicine.