Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance

Abstract

Objective This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large‐scale emerging evidence. Background Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. New/updated hypothesis We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. Major challenges for the hypothesis While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti‐ferroptotic/iron compound in AD patients. Linkage to other major theories Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well‐established consequence of aging and inflammation, which are major theories of disease pathogenesis.

The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing

“…In aged wild-type mice, as well as an APP transgenic mouse model, a highiron diet induces Aβ production [66] and we show that a similar diet increases the binding of Lf to APP. Part of the innate immune role of Lf during a pathogen invasion is to deplete extracellular iron essential for pathogen replication [35] and therefore the burden of brain iron that drives the onset of sporadic AD [67][68][69] may particularly receive contributions from activated microglia [70][71][72], and is likely also to increase the proportion of iron-loaded holo-Lf within the interstitial space. Subsequently, the elevated holo-Lf would promote amyloidogenic processing of APP and thus contribute to amyloid pathology.…”

Nerve Growth Factor-Based Therapy in Alzheimer’s Disease and Age-Related Macular Degeneration

“…High ferritin levels suggest an increase of Fe abundance in the CSF and brain which can be associated with ferroptosis, an iron-dependent cell death that results from a buildup of lipid peroxides and is regulated by glutathione (GSH) peroxidase 4 ( Acevedo et al, 2019 ). A recent study provided a very interesting theoretical significance of abnormalities of Fe associated with AD onset and progression ( Ayton et al, 2021 ). Fe and Cu metabolism are intertwined in physiology, and they are certainly tied in AD ( Squitti et al, 2010 ).…”

Microglia and Astrocytes in Alzheimer’s Disease in the Context of the Aberrant Copper Homeostasis Hypothesis

“…GSH depletion has been pointed out as the main driver of ferroptosis in AD, which is a special modality of cell death determined by an iron-dependent phospholipid peroxidation [ 106 ]. The drop in GSH provides a link between Cu imbalance and iron dysmetabolism tied to AD risk and progression [ 107 ]. The expression of Cu-dependent enzymes, such as Cu/Zn SOD1 and antioxidant protein 1 (ATOX1), was markedly reduced in multiple microarray studies of AD patients, reinforcing the notion that a lack of Cu, by reducing host antioxidant defenses, plays a pivotal role in AD pathology [ 108 , 109 ].…”