Plasma transferrin and hemopexin are associated with altered Aβ uptake and cognitive decline in Alzheimer’s disease pathology

Abstract

Background: Heme and iron homeostasis is perturbed in Alzheimer's disease (AD); therefore, the aim of the study was to examine the levels and association of heme with iron-binding plasma proteins in cognitively normal (CN), mild cognitive impairment (MCI), and AD individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohorts. Methods: Non-targeted proteomic analysis by high-resolution mass spectrometry was performed to quantify relative protein abundances in plasma samples from 144 CN individuals from the AIBL and 94 CN from KARVIAH cohorts and 21 MCI and 25 AD from AIBL cohort. ANCOVA models were utilized to assess the differences in plasma proteins implicated in heme/iron metabolism, while multiple regression modeling (and partial correlation) was performed to examine the association between heme and iron proteins, structural neuroimaging, and cognitive measures. Results: Of the plasma proteins implicated in iron and heme metabolism, hemoglobin subunit β (p = 0.001) was significantly increased in AD compared to CN individuals. Multiple regression modeling adjusted for age, sex, APOEε4 genotype, and disease status in the AIBL cohort revealed lower levels of transferrin but higher levels of hemopexin associated with augmented brain amyloid deposition. Meanwhile, transferrin was positively associated with hippocampal volume and MMSE performance, and hemopexin was negatively associated with CDR scores. Partial correlation analysis revealed lack of significant associations between heme/iron proteins in the CN individuals progressing to cognitive impairment. Conclusions: In conclusion, heme and iron dyshomeostasis appears to be a feature of AD. The causal relationship between heme/iron metabolism and AD warrants further investigation.

Low Cerebrospinal Fluid Levels of Hemopexin Are Associated With Increased Alzheimer's Pathology, Hippocampal Hypometabolism, and Cognitive Decline

“…Moreover, CSF Hb subunits were significantly higher in MCI-c compared to MCI-nc and were associated with decreased CSF Aβ and increased CSF ptau. The present CSF study extends our recent plasma study (Ashraf et al, 2020a), and solidifies evidence for the involvement of heme/iron dyshomeostasis in the pathogenesis of AD.…”

“…This is consistent with the association of low CSF HPX levels with low CSF Aβ, high CSF ptau, increased glucose hypometabolism and cognitive decline, i.e., disease progression (although not MCI conversion to AD). In our previous study (Ashraf et al, 2020a), plasma HPX was associated with brain amyloid deposition, albeit from a different cohort. HPX is an abundant plasma protein that is also expressed by both neurons and glia (Morris et al, 1993), with the majority of CSF HPX produced intrathecally in normal human subjects (Garland et al, 2016).…”

“…HPX is an abundant plasma protein that is also expressed by both neurons and glia (Morris et al, 1993), with the majority of CSF HPX produced intrathecally in normal human subjects (Garland et al, 2016). While matched plasma and CSF were not available from the present cohort, considering our previous plasma (Ashraf et al, 2020a) and current CSF HPX findings, we suggest the decreased CSF HPX associated with decreased CSF Aβ and increased ptau, and disease progression (albeit not MCI conversion to AD), may result from: abnormally greater HPX export from the CSF to the plasma compartment; decreased neuroglial HPX synthesis; and/or increased brain parenchymal low density lipoprotein receptor-related protein 1 (LRP1)mediated scavenging (Hvidberg et al, 2005). Interestingly, LRP1 is rather a promiscuous receptor and APOE and Aβ are all ligands (Ashraf et al, 2019a) as well as HPX (Hvidberg et al, 2005).…”

“…We have recently documented increased plasma hemopexin levels to be associated with increased brain amyloid uptake as measured by 18F -florbetaben position emission tomography (amyloid PET), in a cohort comprising cognitively normal (CN), MCI and AD (Ashraf et al, 2020a). Moreover, increased plasma HPX was associated with a lower clinical dementia rating (CDR), suggestive of improved cognition.…”

Machine Learning Profiling of Alzheimer's Disease Patients Based on Current Cerebrospinal Fluid Markers and Iron Content in Biofluids

“…Emerging evidence suggested that blood iron homeostasis is altered in AD and already in MCI (Faux et al, 2014 ; Ashraf et al, 2020 ; Guan et al, 2020 ), including systemic variation of markers of iron metabolism, such as transferrin saturation and ceruloplasmin/transferrin ratio in serum (Squitti et al, 2010 ). Interestingly, in our case, we found a negative correlation between t-Tau and Tf in serum in AD that can support a role of Tf in neurodegeneration.…”