Elevated plasma p-tau181 levels unrelated to Alzheimer’s disease pathology in amyotrophic lateral sclerosis

Abstract

BackgroundPhosphorylated-tau181 (p-tau181), a specific marker of Alzheimer’s disease (AD) pathology, was found elevated in plasma but not in cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). We expanded these findings in a larger patient cohort, exploring clinical/electrophysiological associations, prognostic value and longitudinal trajectories of the biomarker.MethodsWe obtained baseline plasma samples from 148 ALS, 12 spinal muscular atrophy (SMA), and 88 AD patients, and 60 healthy controls. Baseline CSF and longitudinal plasma samples were from 130 and 39 patients with ALS. CSF AD markers were measured with the Lumipulse platform, and plasma p-tau181 with SiMoA.ResultsPatients with ALS showed higher plasma p-tau181 levels than controls (p<0.001) and lower than AD participants (p=0.02). SMA patients had higher levels than controls (p=0.03). In patients with ALS, CSF p-tau and plasma p-tau181 did not correlate (p=0.37). Plasma p-tau181 significantly increased with the number of regions showing clinical/neurophysiological lower motor neurons (LMN) signs (p=0.007) and correlated with the degree of denervation in the lumbosacral area (r=0.51, p<0.0001). Plasma p-tau181 levels were higher in classic and LMN-predominant than in bulbar phenotype (p=0.004 and p=0.006). Multivariate Cox regression confirmed plasma p-tau181 as an independent prognostic factor in ALS (HR 1.90, 95% CI 1.25 to 2.90, p=0.003). Longitudinal analysis showed a significant rise in plasma p-tau181 values over time, especially in fast progressors.ConclusionsPlasma p-tau181 is elevated in patients with ALS, independently from CSF levels, and is firmly associated with LMN dysfunction. The finding indicates that p-tau181 of putative peripheral origin might represent a confounding factor in using plasma p-tau181 for AD pathology screening, which deserves further investigation.

Amyloid-Beta Co-Pathology Is a Major Determinant of the Elevated Plasma GFAP Values in Amyotrophic Lateral Sclerosis

“…This probably reflects the strong relationship between activated astrocytes and amyloid plaques in AD patients' brains [15,24]. In this view, plasma GFAP could serve as a valid surrogate blood biomarker for the identification of AD co-pathology in ALS patients, given the suboptimal value of plasma p-tau181 in these subjects due to its likely peripheral source, as already demonstrated in two studies [22,25] and confirmed in this work in a larger cohort. Plasma GFAP showed the highest accuracy among the examined plasma biomarkers in identifying ALS patients with positive amyloid status and full-blown AD pathology.…”

“…These data reflect the lack of correlation of plasma GFAP with scores of motor impairment severity, which plays the most important role in determining the disease course. Notably, plasma GFAP retained its prognostic value when we only accounted for plasma NfL, and p-tau181, which were previously shown to predict survival in ALS patients [ 4 , 5 , 22 ]. This confirms the specific prognostic contribution of this biomarker, possibly indicating cognitive impairment, and suggests that prognostic estimates based on different blood biomarkers, with p-tau181 mainly reflecting LMN degeneration and NfL expressing the overall disease severity, may have an added value in ALS patients.…”

“…Higher plasma GFAP values in females were previously reported in ALS patients, albeit potentially related to the older age [ 19 ], and in subjects with other neurodegenerative disorders as well [ 12 , 13 ]. However, such a difference was not highlighted in other patient groups [ 22 ]. In our cohort, the slightly higher plasma GFAP values in females could be at least partially related to the higher prevalence of beta-amyloid co-pathology (A+, females 15.5%, males 11.2%).…”

The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

“…Several ptau isoforms exist that could be utilized to study Alzheimer’s disease (AD) pathology ( Suárez-Calvet et al ., 2020 ; Hirota et al ., 2022b ; Salvadó et al ., 2024 ). Numerous studies have explored the utility of these markers over the years, often yielding conflicting results ( Hampel et al ., 2004 ; Vacchiano et al ., 2023 ; Ingannato et al ., 2024 ; Salvadó et al ., 2024 ). Consequently, there is still debate regarding the best marker for AD, and new candidates are continually being proposed ( Suárez-Calvet et al ., 2020 ; Karikari et al ., 2021 ; Salvadó et al ., 2024 ).…”

“…( Janelidze et al ., 2023 ). Furthermore, CSF-based ptau181 is not influenced by other neurological conditions, unlike its plasma counterpart ( Vacchiano et al ., 2023 ), and captures clear AD signatures compared to other dementias. ( Zetterberg, 2017 ).…”