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 AD. This project will enable many
exciting opportunities to test new therapies before the onset of memory decline.