# Brain-injury and Alzheimer’s disease biomarkers are elevated in patients with suspected infection and physiological derangement: importance for context-specific interpretation of Alzheimer’s biomarkers

## TL;DR

The study finds that brain injury and Alzheimer's biomarkers are elevated in patients with suspected infection, suggesting these biomarkers may be influenced by non-brain factors like infection.

## Contribution

The paper is the first to show that p-tau-217, a key Alzheimer’s biomarker, is elevated in sepsis patients, potentially complicating its use in diagnosing Alzheimer’s.

## Key findings

- Total tau and NfL levels were significantly higher in suspected sepsis patients compared to controls.
- p-tau-217 levels in sepsis patients were comparable to those in Alzheimer’s disease patients.
- Serum total tau levels correlated strongly with cytokine profiles in sepsis patients.

## Abstract

Following acute infective illness, patients frequently exhibit neurological symptoms, with persistent neurological symptoms commonly observed following severe infection. However, the association between systemic infection and the concentration of blood-based biomarkers of brain injury and the relationship between these and markers of the host response to infection are poorly characterized in the literature. Further, the association between acute illness and the Alzheimer’s disease–associated biomarker phosphorylated-tau-217 (p-tau-217) is unknown. In acute samples from 26 patients attending the emergency department with suspected sepsis (clinically suspected or proven infection, a National Early Warning Score or National Early Warning Score 2 score ≥ 5), the levels of serum biomarkers of brain injury (neurofilament light [NfL], glial fibrillary acidic protein (GFAP), total tau and ubiquitin C-terminal hydrolase L1) and p-tau-217 were compared to age- and sex-matched non-infected controls, with further assessment of the correlation between the biomarker levels and cytokine profiles. p-tau-217 levels were additionally compared to a positive control group of patients with diagnosed Alzheimer’s disease. Both total tau (P = 0.006, Wilcoxon rank-sum test) and NfL (P = 0.044, Wilcoxon rank-sum test) levels were significantly higher in patients with suspected sepsis as compared to controls, with no significant differences in levels of GFAP or ubiquitin C-terminal hydrolase L1. Within suspected sepsis patients, serum total tau levels were associated with multiple cytokines and a summary cytokine score (Spearman’s rank correlation coefficient ρ = 0.65, P < 0.001). There were significantly higher p-tau-217 levels in suspected sepsis patients as compared to non-infected controls (P < 0.001, Dunn–Kruskal–Wallis test), with no significant difference compared to Alzheimer’s disease controls (P = 0.118, Dunn–Kruskal–Wallis test). Of patients with suspected sepsis, 29% had a p-tau-217 level classified as high (>0.63 pg/ml) with a further 17% classified as intermediate (0.4–0.63 pg/ml). In conclusion, we have identified elevated levels of total tau and NfL compared to age- and sex-matched controls, along with significant correlations between these tau levels and cytokine levels. Additionally, we observed elevated levels of p-tau-217 in the patient cohort, with levels comparable to those seen in Alzheimer’s disease patients. Further analysis is required to replicate the findings of this study in larger cohorts. However, the results suggest a potentially extracranial source of tau expression in the context of infection or physiological stress. Given the potential for acute illness to influence p-tau-217 levels, our results raise important considerations regarding the interpretation of p-tau-217 as a diagnostic marker for Alzheimer’s disease in patients with active infection.

Whitehouse et al. report elevations in brain-injury and Alzheimer’s disease biomarkers in patients with suspected sepsis. This exploratory secondary analysis of the ABC-Sepsis study indicates that acute infection and/or physiological stress may elevate biomarker levels, including total tau and p-tau-217, potentially confounding their interpretation in diagnostic or research contexts.

Graphical Abstract