Dataset Information

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.

SUBMITTER: Ayton S

PROVIDER: S-EPMC9701539 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Ayton Scott S Portbury Stuart S Kalinowski Pawel P Agarwal Puja P Diouf Ibrahima I Schneider Julie A JA Morris Martha Clare MC Bush Ashley I AI

Alzheimer's & dementia : the journal of the Alzheimer's Association 20210125 7

<h4>Objective</h4>This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large-scale emerging evidence.<h4>Background</h4>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 ...[more]

PMID: 33491917

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Project description:ImportanceTelomere length has been associated with dementia and psychological stress, but its relationship with human brain size is unknown.ObjectiveTo determine if peripheral blood telomere length is associated with brain volume.Design, setting, and participantsPeripheral blood leukocyte telomere length and brain volumes were measured for 1960 individuals in the Dallas Heart Study, a population-based, probability sample of Dallas County, Texas, residents, with a median (25th-75th percentile) age of 50 (42-58) years. Global and 48 regional brain volumes were assessed from the automated analysis of magnetic resonance imaging.Main outcomes and measuresTelomere length and global and regional brain volumes.ResultsLeukocyte telomere length was associated with total cerebral volume (β [SE], 0.06 [0.01], P <.001) including white and cortical gray matter volume (β [SE], 0.04 [0.01], P = .002; β [SE], 0.07 [0.02], P <.001, respectively), independent of age, sex, ethnicity, and total intracranial volume. While age was associated with the size of most subsegmental regions of the cerebral cortex, telomere length was associated with certain subsegmental regions. Compared with age, telomere length (TL) explained a sizeable proportion of the variance in volume of the hippocampus, amygdala, and inferior temporal region (hippocampus: βTL [SE], 0.08 [0.02], R2, 0.91% vs βage [SE], -0.16 [0.02], R2, 3.80%; amygdala: βTL [SE], 0.08 [0.02], R2, 0.78% vs βage [SE],-0.19 [0.02], R2,4.63%; inferior temporal: βTL [SE], 0.07 [0.02], R2, 0.92% vs βage [SE], -0.14 [0.02], R2, 3.98%) (P <.001 for all). The association of telomere length and the size of the inferior and superior parietal, hippocampus, and fusiform regions was stronger in individuals older than 50 years than younger individuals (inferior parietal: β>50 [SE], 0.13 [0.03], P <.001 vs β≤50 [SE], 0.02 [0.02], P = .51, P for interaction = .001; superior parietal: β>50 [SE], 0.11 [0.03], P <.001 vs β≤50 [SE], 0.01 [0.02], P = .71, P for interaction = .004; hippocampus: β>50 [SE], 0.10 [0.03], P = .004 vs β≤50 [SE], 0.05 [0.02], P = .07, P for interaction = .04; fusiform: β>50 [SE], 0.09 [0.03], P = .002, β≤50 [SE], 0.03 [0.02], P = .31, P for interaction = .03). The volume of the hippocampus, amygdala, superior and inferior temporal, precuneus, lateral orbitofrontal, posterior cingulate, thalamus and ventral diencephalon were independently associated with telomere length after adjustment for all covariates (age, gender, ethnicity, total intracranial volume, body mass index, blood pressure, diabetes, smoking status, and APOE genotype).Conclusions and relevanceTo our knowledge, this is the first population-based study to date to evaluate telomere length as an independent predictor of global and regional brain size. Future studies are needed to determine how telomere length and anatomic structural changes are related to cognitive function, dementia, and psychological disease.

Dataset Information

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

Objective

Background

New/updated hypothesis

Major challenges for the hypothesis

Linkage to other major theories

Publications

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

Similar Datasets

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