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.