See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-β by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-β to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-β load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-β positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [β(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [β(standard error) = -0.139 (0.048), P = 0.004), and attention [β(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [β(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [β(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-β to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-β positron emission tomography to stratify individuals at risk of decline.

Cortical iron has been shown to be elevated in Alzheimer’s disease (AD), but the impact of 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[S.E.]=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. Whereas 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[S.E.]=−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.