Alzheimer’s disease (AD) afflicts millions of Americans, but no effective treatments exist. Although abnormal proteins (amyloid and tau) accumulate and accompany neurodegeneration in AD, recent studies suggest that inflammation led by the brain’s immune cells (microglia) is an important factor. However, inflammation is challenging to measure in living patients. Iron is a key component of inflammation and may be toxic in AD. Because it can be measured by MRI, iron may be a practical surrogate measure for inflammation. Coupling MRI with pathology slides has shown that iron is present within microglia in AD, in particular in a part of the brain important for memory, the hippocampus. This project proposes that iron-containing microglia accumulate early in the disease process. The end result of this inflammation could be tau accumulation and neuronal death. If iron-containing microglia can be detected by MRI early in the disease process, before memory has become too impaired, this could revolutionize AD diagnosis and treatment. The project goals are as follows. (1) Determine whether the accumulation of iron-containing microglia is concomitant with widespread amyloid deposition and antecedent to tau propagation. This project will examine the post-mortem hippocampus of patients with and without AD pathology. By combining MRI with a careful examination of pathology slides, this project will prove that MRI is measuring iron-containing microglia across the stages of AD. We will also see how the iron, microglia, amyloid, and tau overlap with one another in human brain specimens. (2) Determine whether iron is higher in the hippocampus in AD compared to no AD using advanced microscopy. This project will employ X-ray microscopy and electron microscopy to measure exactly how much iron is in the hippocampus, and to define the precise location where it is increased in AD. (3) Determine whether iron-containing microglia are present along with amyloid and tau in living AD patients, present with along amyloid in patients with mild or no AD symptoms, and absent in patients with no amyloid. This proposal will recruit patients with AD, patients with mild cognitive impairment, and healthy control participants from Stanford’s Alzheimer’s Disease Research Center. We will balance for gender and age across groups, perform a full neuropsychological evaluation, and obtain APOE status. Participants will undergo three studies: a 7T GRE MRI, an amyloid PET-MR scan, and a tau PET-MR scan. This project will show how iron-containing microglia, amyloid, and tau overlap with one another in living humans. The contribution of this project will be to show that 7T GRE MR measures iron-containing microglia. This measurement can serve as an effective biomarker for inflammation in early ...