The background to this research
The diagnosis of Alzheimer's disease in vivo could now be achieved with high accuracy through the use of biofluid and neuroimaging biomarkers.
Phosphorylated (p)-tau is a biofluid diagnostic biomarker for Alzheimer's disease (AD) that is typically elevated in the cerebrospinal fluid (CSF) of AD patients compared to controls and other neurological diseases. There are several CSF p-tau species, the most studied being p-tau 181 and 217. Several studies have shown, that, highly sensitive assays can measure p-tau 181 and p-tau 217 in blood (serum or plasma) with very high accuracy for AD pathology.
Therefore, these proteins have been proposed as potential screening tests for AD pathology in the general population and have recently been included in the Revised criteria for diagnosis and staging of AD (Jack et al. 2024). With the advent of new therapies for AD, such as anti-amyloid monoclonal antibodies, the identification of AD pathology in the asymptomatic and early symptomatic stages of the disease will become increasingly important.
However, a few studies published between 2022 and 2023 (Cousins et al. 2022; Vacchiano et al. 2023, Verde et al. 2023) have reported that even patients with amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with motor neuron degeneration, may have high levels of blood p-tau 181 (in the presence of normal CSF biomarker concentrations) compared to controls. Furthermore, these studies hypothesized the existence of a peripheral source for blood p-tau elevation in ALS without definitively identifying this source.
Taken together, these studies raised questions about the specificity of blood p-tau biomarkers for AD pathology and prompted us to investigate on this issue further.
Key findings from our research
Our laboratory has a long history of investigating the diagnostic and prognostic role of CSF and blood biomarkers in neurodegenerative diseases, such as ALS and AD.
In the present study, we measured serum p-tau 181 and p-tau 217 in a large multicentre cohort of ALS and AD cases and disease controls (subjects without clinical, neuroradiological and CSF evidence of neurodegenerative disease). In addition, we looked for a potential peripheral source of blood p-tau elevation in ALS patients by analysing ALS and control muscle biopsies using mass spectrometry and immunohistochemistry.
We found higher serum p-tau 181 and p-tau 217 levels in AD and ALS patients compared to disease controls. We also reported strong correlations between blood p-tau 181 and p-tau 217 and blood troponin T, a marker of muscle damage, and confirmed the lack of correlation between CSF and serum p-tau 181 levels in ALS. All these findings strengthened the hypothesis of a peripheral source of p-tau 181 elevation in ALS.
When we looked at muscle biopsies, our immunohistochemical and mass spectrometry analyses revealed the presence of p-tau 181 and 217 in muscle biopsies from both ALS cases and disease controls. Most interestingly, ALS muscle samples showed increased p-tau reactivity in atrophic muscle fibres.
Thus, we suggested that the elevation of serum p-tau 181 and p-tau 217 in ALS likely reflects protein release from denervated muscle fibres.
Implications for future research
On the one hand, our data highlight the role of blood p-tau 181 and p-tau 217 as candidate biomarkers, not only for AD but also for ALS. This should be further investigated in longitudinal studies, also taking into account their potential prognostic value.
On the other hand, it is evident that blood p-tau concentrations assessed with currently available commercial assays may be influenced by the confounding measurement of species of peripheral origin. This problem could have an impact on the use of blood p-tau species for screening in the pre-symptomatic and early stages of neurodegenerative diseases.