Researchers report that blood levels of phosphorylated tau – biomarkers widely studied in Alzheimer's disease – are elevated in patients with immunoglobulin light chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis. The findings, in Nature Medicine, suggest that circulating phosphorylated tau may have potential as a blood-based biomarker to support diagnosis of systemic amyloidosis, particularly in patients presenting with unexplained neuropathy.
Systemic amyloidoses are protein misfolding disorders characterized by deposition of amyloid fibrils in tissues and organs. In AL amyloidosis, the fibrils arise from misfolded immunoglobulin light chains produced by plasma cells. In ATTR amyloidosis, amyloid forms from misfolded transthyretin protein, either due to inherited variants or age-related accumulation of the wild-type protein. Both conditions frequently affect peripheral nerves and can present with progressive polyneuropathy.
Diagnosis typically involves a combination of clinical evaluation, laboratory testing, imaging, and tissue biopsy. Because symptoms such as neuropathy overlap with many other disorders, there is ongoing interest in identifying blood-based biomarkers that could assist in earlier or more targeted diagnosis.
In the study, investigators analyzed serum samples from 280 individuals across four clinical cohorts in Italy, Germany, and the Netherlands. Participants included patients with AL amyloidosis, patients with ATTR amyloidosis (both hereditary and wild-type forms), individuals with polyneuropathy unrelated to amyloidosis, and control participants without neuropathy or amyloidosis.
The researchers measured phosphorylated tau at position 181 (p-tau181) in blood samples. Levels of this biomarker were consistently higher in patients with AL or ATTR amyloidosis than in controls. In pooled analyses adjusted for age and sex, p-tau181 demonstrated moderate diagnostic discrimination, with an area under the receiver operating characteristic curve of 0.82.
Elevated p-tau181 levels were also associated with amyloidosis-related neuropathy. Patients with neuropathy caused by AL or ATTR amyloidosis had higher biomarker levels, whereas individuals with neuropathy from other causes did not show comparable increases. This pattern suggests that phosphorylated tau could help differentiate amyloid-associated neuropathy from other peripheral nerve disorders.
The investigators also measured another phosphorylated tau species, p-tau217, in a subset of samples. Although present at lower concentrations, p-tau217 showed a similar pattern of elevation in patients with amyloidosis and also distinguished these cases from controls.
A small group of individuals carrying pathogenic ATTR variants but without symptoms was also evaluated. In these participants, p-tau181 levels increased as individuals approached their predicted age of disease onset, suggesting that the biomarker may change during early stages of disease.
Phosphorylated tau is primarily used in research on neurodegenerative diseases such as Alzheimer's disease. The authors note that elevated levels in systemic amyloidosis may reflect broader cellular responses to amyloid deposition in tissues such as peripheral nerves or cardiac muscle.
Overall, the study indicates that circulating phosphorylated tau may have potential diagnostic value in systemic amyloidosis and could support evaluation of patients with suspected amyloid-related neuropathy. Further studies will be needed to determine how these biomarkers could be incorporated into diagnostic workflows.
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