Iron Spreading Patterns in Alzheimer's Disease

We know that iron accumulates in the brains of patients with Alzheimer’s Disease. This process strongly predicts how fast a patient’s cognitive function will decline. However, we do not yet know where in the brain the accumulation starts, and how the accumulation spreads. That makes it difficult to develop measurements that can help to predict the disease course for individual patients. In this project we will develop an atlas of the brain that shows how iron accumulates as Alzheimer’s Disease progresses over time. We do that by studying hundreds of brain donors with varying degrees of AD.

Aim 1: Analyse how iron spreads in Alzheimer’s Disease patients by a sensitive staining that visualises iron in brain tissue. Based on these stainings, we will build an atlas that depicts iron accumulation in the brain in relation to other hallmarks of Alzheimer’s Disease, such as amyloid and tau spreading. Aim 2: Study whether iron accumulation is correlated to cognitive decline and will improve the prediction of disease progression. Lastly, we will study gene expression in patients with different amounts of iron accumulation to determine which pathways are involved.

We already demonstrated that iron in the human cortex is highly correlated with pathology, and with cognitive decline in Alzheimer’s Disease patients. However, we have poor understanding of the pattern of iron accumulation over the brain cortex, nor of its progression with disease duration. In this project we will develop a pathological staging system (similar to the Braak staging) for iron, and make a standardized map of iron accumulation over the different stages of AD, which will form the basis for pathologists, neurologists and scientists to quantify iron accumulation in the brain.

We intend that our methods and maps will become the standard for iron staging in AD, thus unifying and standardizing the rapidly increasing research field.

Based on the staging system we will develop here on gold-standard pathology, we will use this system to correlate the pathology findings to in vivo MRI scans that reflect iron in the brain.

Lastly, in this grant we will correlate post-mortem iron spreading patterns to cognitive decline before death. These data will inform studies into iron MRI biomarkers that may predict the disease trajectory, additional to tau or amyloid pathology.