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


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.

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This study was supported by grants from the National Institute of Health (R01AG017917, R21E2021290, and RF1AG054057). The analysis was supported by funds from the Australian Research Council, the Australian National Health & Medical Research Council (NHMRC), and the Cooperative Research Centre for Mental Health (the Cooperative Research Centre program is an Australian Government Initiative). The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government, in particular, funding from the Operational Infrastructure Support Grant. No funder of this study had any role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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SA: scientific concept, writing the manuscript, directing the analysis. YW: performed statistical analysis. ID: performed statistical analysis, graphed the results. JB: measured iron, edited the manuscript. JAS: performed neuropathology, edited the manuscript. MCM: scientific concept, funding, writing the manuscript. AIB: scientific concept, funding, writing the manuscript.

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Correspondence to Martha Clare Morris or Ashley I. Bush.

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Conflict of interest

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.

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Ayton, S., Wang, Y., Diouf, I. et al. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry 25, 2932–2941 (2020).

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