Iron and Alzheimer’s Disease: From Pathology to Imaging

Abstract

Alzheimer’s disease (AD) is a debilitating brain disorder that afflicts millions worldwide with no effective treatment. Currently, AD progression has primarily been characterized by abnormal accumulations of β-amyloid within plaques and phosphorylated tau within neurofibrillary tangles, giving rise to neurodegeneration due to synaptic and neuronal loss. While β-amyloid and tau deposition are required for clinical diagnosis of AD, presence of such abnormalities does not tell the complete story, and the actual mechanisms behind neurodegeneration in AD progression are still not well understood. Support for abnormal iron accumulation playing a role in AD pathogenesis includes its presence in the early stages of the disease, its interactions with β-amyloid and tau, and the important role it plays in AD related inflammation. In this review, we present the existing evidence of pathological iron accumulation in the human AD brain, as well as discuss the imaging tools and peripheral measures available to characterize iron accumulation and dysregulation in AD, which may help in developing iron-based biomarkers or therapeutic targets for the disease.

Myelin repair in Alzheimer’s disease: a review of biological pathways and potential therapeutics

“…Additionally, clinical neuroimaging studies have demonstrated the association between iron accumulation and myelination in normal aging [ 140 , 141 ] as well as the association between tau accumulation and iron in AD patients [ 142 ]. Cerebrospinal fluid levels of iron transport proteins are also associated with cognitive decline in AD [ 137 ].…”

“…Inflammatory milieu such as the presence of activated microglia and associated cytokine production may also play a role in inducing ferritin toxicity to OLs [ 144 ]. Additionally, excess iron in animal models can increase APP, inhibit α-secretase cleavage, and increase β-secretase cleavage [ 137 ]; however, APP, in turn, can stabilize the iron export protein ferroportin (Fpn) [ 137 , 148 ], which is involved in OL maturation and myelination [ 149 ]. Another iron import protein, Divalent metal transporter 1, is involved in APP processing and co-localizes with Aβ plaques [ 150 ], and its deletion is associated with reductions in OPC maturation and myelination [ 147 ].…”

“…Iron homeostasis is essential for glial function and myelination, and multiple recent literature reviews implicate dysfunctional iron homeostasis in the pathogenesis of AD [137][138][139]. Additionally, clinical neuroimaging studies have demonstrated the association between iron accumulation and myelination in normal aging [140,141] as well as the association between tau accumulation and iron in AD patients [142].…”

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer’s Disease Progression

“…A plaques have been considered for many years as the main cause of neurotoxicity in AD onset and progression, but development of A plaques is a common phenomenon in most people during aging and does not necessarily lead to cognitive decline. As a matter of fact, based on postmortem analyses, individuals with A plaques and large Fe deposits are highly likely to develop dementia [ 56 ], possibly implicating that a tendency towards brain Fe accumulation could be a factor increasing AD susceptibility. In addition, during the onset of AD, microglial cells are believed to protect the brain by incorporating extracellular A filaments that are prone to bind several metals, such as Cu, Zn and Fe [ 49 , 57 ], until their maximum buffering capacity [ 57 ].…”

Bibliometric analysis of research on Alzheimer’s disease and non-coding RNAs: Opportunities and challenges

“…Alzheimer’s disease (AD) is a neurodegenerative disease with insidious onset, characterized by progressive cognitive dysfunction and memory impairment ( Morató et al, 2022 ). The main pathological features of AD are decreased a number of cortical neurons, nerve fiber tangles, and senile plaque deposition ( Counil and Krantic, 2020 ; Tran et al, 2022 ). With the increase of age, the incidence of AD increases gradually, which seriously affects the quality of life and brings a great burden to families.…”