Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer's disease: a potential early sign of AD

Abstract

Background: Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer's disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers.

Methods: Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) (N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (Aβ42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers.

Results: In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype.

Conclusion: We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated.

Trial registration: ClinicalTrials.gov NCT01041989 . Registered on 4 January 2010-retrospectively registered.

Keywords: Aging; Alzheimer’s disease; ApoE4; Dementia; Inflammation; Thioredoxin-80.

Fig. 1

A CONSORT diagram of the FINGER exploratory Thioredoxin-80 sub-study. CERAD, Consortium to Establish a Registry for Alzheimer’s Disease. B Serum Trx80 levels by disease diagnosis. Participants were divided into four groups according to their disease state. FINGER cohort participants and SCI, MCI, and AD participants from the GEDOC cohort. The graph shows serum Trx80 levels (ng/ml) between groups. p values are calculated from one-way ANCOVA adjusted for age. C Hippocampal volume of patients with highest and lowest serum Trx80 levels in FINGER cohort. The graph shows hippocampal volume (ml) between groups. t-test was used to analyze the differences between groups. D Serum Trx80 levels in ApoE4 carriers and non-carriers from merged GEDOC and FINGER cohorts. The graph shows serum Trx80 levels (ng/ml) between groups. p values are calculated from one-way ANCOVA adjusted for age. E Western-bot analysis of Trx80 levels in post-mortem AD and non-AD brain samples. Samples are sorted by APOE genotype ApoE3/ApoE3 (E3/E3) and E4/E4. Student t-test was used to analyze the differences between groups. *p < 0.05; **p < 0.01; ****p < 0.0001