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.

Keywords: Alzheimer's disease; cognitive decline; iron; neurodegeneration; pathology.

Figure 1.. Iron levels in different brain regions of donors stratified by clinical and pathological (CERAD) diagnosis of AD.

Statistics are from multiple regression models of iron in each region in strata of pathological diagnosis, and including the following covariates: age, sex, APOE ε4 and clinical diagnosis.

Figure 2.. Association between brain iron and cognitive change in donors with CERAD-confirmed AD pathology, with and without clinical diagnosis of dementia.

Association between linear and quadratic terms of (A,D) iron composite, (B,E) NFTs and (C,F) plaque deposition with change in the Global Cognitive composite in the 10 years prior to death of donors who had CERAD-confirmed AD pathology with (A-C) and without (D-F) a clinical diagnosis of dementia. Data was modelled using continuous variables, but these were represented in tertiles for visual display.

Figure 3.. Current and Proposed Iron hypothesis of AD (simplified).

(A)The previous hypothesis was that iron promotes plaque and tangle formation by promoting APP and tau production as well as aggregation of Aβ and phospho-tau. Brain iron levels may be impacted by aging, changes in APP processing, inflammation and vascular damage. Iron trapped within these protein pathologies augmented toxicity through generating reactive oxygen species. Our current findings from a large longitudinal cohort confirmed that tissue iron burden may impact on the formation of NFTs, at least in the inferior temporal cortex. Our current investigation of bulk tissue levels of iron does not uphold a relationship between bulk tissue iron burden and amyloid formation. However, this study was unable to test the impact of iron in microvicinities, where previous findings indicate that iron is markedly enriched in plaques and tangles. Loss of tau function can, in its own right, cause neuronal iron accumulation. The new data lead us to further update the hypothesis, where iron has an additional role downstream of proteinopathy, by influencing the susceptibility of neurons to die (or cause synaptic damage) due to ferroptosis. Abnormal iron elevation does not itself cause ferroptosis, rather, the burden of iron in the tissue renders neurons more susceptible to ferroptotic stress. Therefore, people with relatively more iron, but still within the normal range, are likely to deteriorate faster during disease. (B) Ferroptosis pathways. Glutathione, which is depleted in AD brain tissue [51, 60, 68], prevents ferroptosis by providing substrate for the ferroptosis checkpoint selenoenzyme, GPX4. GPX4 detoxifies lipid hydroperoxides that are formed by cytoplasmic iron reacting with membrane PUFAs, otherwise cell rupture ensues. Cystine enters neurons via the system Xc⁻ antiporter in exchange for glutamate that is exported. Cystine is reduced to cysteine within the cell, which is the rate limiting amino acid for glutathione synthesis. Low cysteine levels promote ferroptosis by both depleting glutathione, and by promoting ferritin degradation that releases cytoplasmic iron to fuel the peroxidation reaction [69]. The more iron in the cell, the greater the vulnerability toward ferroptosis. Lipid peroxides in ferroptosis lead to downstream products such as hydroxynonenal, malondialdehyde, F₂-isoprostanes, acrolein, with subsequent depletion of long-chain PUFA depletion- all changes that are reported for AD brain tissue [–76]. The sites of putative therapeutics are noted.