Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Nov;25(11):2932-2941.
doi: 10.1038/s41380-019-0375-7. Epub 2019 Feb 18.

Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology

Scott Ayton  1 , Yamin Wang  2 , Ibrahima Diouf  1   3 , Julie A Schneider  4 , John Brockman  5 , Martha Clare Morris #  6 , Ashley I Bush #  7
Affiliations

Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology

Scott Ayton et al. Mol Psychiatry. 2020 Nov.

Abstract

Cortical iron has been shown to be elevated in Alzheimer's disease (AD), but the impact of the directly measured iron on the clinical syndrome has not been assessed. We investigated the association between post-mortem iron levels with the clinical and pathological diagnosis of AD, its severity, and the rate of cognitive decline in the 12 years prior to death in subjects from the Memory and Aging Project (n = 209). Iron was elevated (β [SE] = 9.7 [2.6]; P = 3.0 × 10-4) in the inferior temporal cortex only in subjects who were diagnosed with clinical AD during life and had a diagnosis of AD confirmed post-mortem by standardized criteria. Although iron was weakly associated with the extent of proteinopathy in tissue with AD neuropathology, it was strongly associated with the rate of cognitive decline (e.g., global cognition: β [SE] = -0.040 [0.005], P = 1.6 × 10-14). Thus, cortical iron might act to propel cognitive deterioration upon the underlying proteinopathy of AD, possibly by inducing oxidative stress or ferroptotic cell death, or may be related to an inflammatory response.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement

AIB is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd, Brighton Biotech LLC, Grunbiotics Pty Ltd, Eucalyptus Pty Ltd, and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd.

Figures

Figure 1.
Figure 1.
Iron levels in the inferior temporal cortex in people stratified by clinical AD diganosis and AD pathological criteria of (A) NIA/Reagan (B) CERAD and (C) Braak.
Figure 2.
Figure 2.. Association between iron and pathology severity.
(A) Association between plaque load and inferior temporal iron in post mortem tissue with background low- or high- AD pathology (by NIA Reagan criteria). High AD pathology indicates classification of moderate or high pathology on NIA/Reagan criteria, Low AD pathology indicates classification of no or low pathology using NIA/Reagan criteria. Data are from multiple regression models of plaque burden with covariates: age, sex, APOE ε4, NFT burden, diagnosis, Lewy Bodies, gross vascular infarcts, and inferior temporal iron level. (B) Association between NFT burden and inferior temporal iron levels in post mortem cases of low- or high- AD pathology. Data are from multiple regression models of NFT burden with covariates: age, sex, APOE ε4, plaque burden, diagnosis, Lewy bodies, gross vascular infarcts, and inferior temporal iron level. Models represent means +/− standard error.
Figure 3.
Figure 3.. Association of iron burden and other neuropathological features with antecedent cognitive decline.
Associations between plaque, NFT and iron (inferior temporal cortex) and change in the global cognition score in the years prior to death in post mortem cases stratified by NIA Reagan criteria into high AD pathology (moderate and high pathology; n=126; A-E) and low AD pathology (no or low pathology; n= 83; F-J). Data are from mixed effects linear models with covariates: age, sex, APOE ε4, plaque burden, NFT, Lewy bodies, gross vascular infarcts, years of education, and inferior temporal iron. Inferior temporal iron, NFT and plaque were included as continuous variables in modeling, but stratified in tertiles for visual display. Lewy bodies and gross infarcts were dichotomous variables (presence/absence). Data are means +/− standard error.
Figure 4.
Figure 4.. NFT burden effect on antecedent cognitive decline mediated by iron in subjects with high AD pathology.
Causal mediation analysis was modeled using a quasi-Bayesian Monte Carlo approximation (mediation package in R), where proportion mediated is calculated from the ratio of the causal mediation effect divided by the total effect.
See this image and copyright information in PMC

References

    1. Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Annals of neurology 1999; 45(3): 358–368. - PubMed
    1. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Archives of neurology 2008; 65(11): 1509–1517. - PMC - PubMed
    1. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006; 66(12): 1837–1844. - PubMed
    1. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006; 67(3): 446–452. - PubMed
    1. Rowe CC, Bourgeat P, Ellis KA, Brown B, Lim YY, Mulligan R et al. Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Annals of neurology 2013; 74(6): 905–913. - PubMed

Publication types