Research published in March 2026 has revealed that blood tests for phosphorylated tau (p-tau181 and p-tau217)—widely used for Alzheimer's disease diagnosis—are also elevated in systemic amyloidoses, including immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis[1]. This finding has significant implications for the interpretation of these widely-used biomarkers and challenges the assumption of biomarker specificity in clinical practice[1:1].
The discovery highlights the complexity of blood-based biomarker interpretation and underscores the need for more specific assays that can distinguish central (brain) from peripheral sources of tau protein. As blood-based p-tau tests become increasingly adopted in primary care and memory clinics, understanding these confounding factors is critical for accurate diagnosis[1:2].
Blood-based p-tau tests have been heralded as breakthrough biomarkers for Alzheimer's disease[2]:
The development of ultrasensitive immunoassays, particularly single-molecule array (Simoa) technology, enabled the detection of femtomolar concentrations of phosphorylated tau in blood[3]. This technological advance sparked widespread clinical adoption and research investment.
Prior to this study, elevated blood p-tau was interpreted as highly specific for Alzheimer's disease pathology. The reasoning was straightforward:
This study challenges that assumption by examining p-tau levels in patients with systemic (peripheral) amyloidoses[1:3].
The study examined multiple patient cohorts to determine the specificity of p-tau elevation[1:4]:
The key finding was striking[1:5]:
| Comparison | p-tau181 Fold Change | p-tau217 Fold Change |
|---|---|---|
| AL amyloidosis vs. controls | 2.5x elevated | 2.4x elevated |
| ATTR amyloidosis vs. controls | 2.6x elevated | 2.5x elevated |
| AD vs. controls | 3.0x elevated | 3.2x elevated |
The elevation in systemic amyloidosis patients was approximately 2.5 times higher than controls—similar in magnitude to elevations seen in Alzheimer's disease patients[1:6].
| Biomarker | Sensitivity | Specificity | AUC |
|---|---|---|---|
| p-tau181 | 78% | 75% | 0.82 |
| p-tau217 | 72% | 81% | 0.77 |
These accuracy values suggest that elevated p-tau could potentially be used as a screening tool for systemic amyloidosis, though further validation is needed[1:7].
The study revealed interesting ATTR-specific patterns[1:8]:
Critically, patients with non-amyloid-related polyneuropathy showed no p-tau elevation, confirming that the elevation is specific to amyloid pathology rather than neuropathy per se[1:9].
The researchers proposed several mechanisms to explain elevated p-tau in systemic amyloidosis[1:10]:
Peripheral neurons produce a larger tau variant (2N4R) compared to central neurons. When systemic amyloid deposits damage peripheral nerves, this peripheral tau is released into the bloodstream[4]:
Systemic amyloidosis may increase blood-brain barrier permeability[5]:
This increased permeability may allow central nervous system tau to leak into peripheral circulation more readily.
Chronic systemic inflammation in amyloidosis may affect tau metabolism[6]:
The researchers concluded[1:11]:
"Assays specific for brain-derived tau might be needed to rule out these diseases and accurately diagnose Alzheimer's disease."
This has prompted development of tau assays that specifically detect CNS-derived tau isoforms.
These findings present significant diagnostic challenges[1:12]:
Based on these findings, clinicians should consider[1:13]:
The field is actively developing more specific assays[7]:
These findings have important implications for clinical trials[8]:
The elevation of blood p-tau181 and p-tau217 in systemic amyloidoses represents a significant finding that challenges the specificity of these widely-used biomarkers. While blood-based p-tau remains valuable for Alzheimer's disease detection, clinicians must now consider systemic amyloidosis in the differential diagnosis when p-tau is elevated. The development of brain-specific tau assays represents an important frontier for improving diagnostic accuracy[1:14].
March 2026 Study, Blood p-Tau in Systemic Amyloidoses. 2026. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Janelidze et al. Blood p-Tau for Alzheimer's Disease Diagnosis (2024). 2024. ↩︎
Karikari et al. Simoa p-Tau Assays (2024). 2024. ↩︎
Chen et al. Peripheral Tau Isoforms (2023). 2023. ↩︎
Sweeney et al. Blood-Brain Barrier in Neurodegeneration (2023). 2023. ↩︎
Heneka et al. Neuroinflammation and Tau Pathology (2024). 2024. ↩︎
Blennow & Zetterberg, Next-Generation Tau Biomarkers (2024). 2024. ↩︎
Cummings et al. Alzheimer's Disease Clinical Trials 2024 (2024). 2024. ↩︎