Abstract
Brain iron dyshomeostasis is a feature of Alzheimer's disease. Conventionally, research has focused on non-heme iron although degradation of heme from hemoglobin subunits can generate iron to augment the redox-active iron pool. Hemopexin both detoxifies heme to maintain iron homeostasis and bolsters antioxidant capacity via catabolic products, biliverdin and carbon monoxide to combat iron-mediated lipid peroxidation. The aim of the present study was to examine the association of cerebrospinal fluid levels (CSF) hemopexin and hemoglobin subunits (α and β) to Alzheimer's pathological proteins (amyloid and tau), hippocampal volume and metabolism, and cognitive performance. We analyzed baseline CSF heme/iron proteins (multiplexed mass spectrometry-based assay), amyloid and tau (Luminex platform), baseline/longitudinal neuroimaging (MRI, FDG-PET) and cognitive outcomes in 86 cognitively normal, 135 mild-cognitive impairment and 66 Alzheimer's participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1) cohort. Multivariate regression analysis was performed to delineate differences in CSF proteins between diagnosis groups and evaluated their association to amyloid and tau, neuroimaging and cognition. A p-value ≤ 0.05 was considered significant. Higher hemopexin was associated with higher CSF amyloid (implying decreased brain amyloid deposition), improved hippocampal metabolism and cognitive performance. Meanwhile, hemoglobin subunits were associated with increased CSF tau (implying increased brain tau deposition). When dichotomizing individuals with mild-cognitive impairment into stable and converters to Alzheimer's disease, significantly higher baseline hemoglobin subunits were observed in the converters compared to non-converters. Heme/iron dyshomeostasis is an early and crucial event in AD pathophysiology, which warrants further investigation as a potential therapeutic target.
Highlights
The amyloid cascade hypothesis remains the major framework for explaining the pathophysiology of Alzheimer’s disease (AD) (Hardy and Higgins, 1992)
Consistent with our hypothesis, we demonstrate higher levels of cerebrospinal fluid levels (CSF) HPX were associated with improved: (1) CSF APOE, (2) CSF Aβ levels, (3) hippocampal glucose metabolism and (4) cognitive performance
CSF Hb subunits were significantly higher in mild cognitive impairment (MCI)-c compared to MCI nonconverters (MCI-nc) and were associated with decreased CSF Aβ and increased CSF ptau
Summary
The amyloid cascade hypothesis remains the major framework for explaining the pathophysiology of Alzheimer’s disease (AD) (Hardy and Higgins, 1992). It assumes a serial model of causality whereby β-amyloid (Aβ) drives tau hyperphosphorylation, resulting in neuronal death and dementia. AD pathology can be present in individuals with mild cognitive impairment (MCI), with 10– 15% of these individuals progressing to AD annually (Petersen et al, 1999). This group displays heterogenicity as not all convert to AD. We have recently provided evidence of a form of iron-dependent cell death termed ferroptosis in post-mortem AD brains (Ashraf and So, 2020; Ashraf et al, 2020b)
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