Project Summary
Dementia is a growing problem in the aging population in the U.S. and worldwide, with prevalence approaching
50% in those older than 85 years old and Alzheimer's disease (AD) is the most frequent cause. Significantly
increased risk for AD dementia is associated with advanced age and carrier-status of the Apolipoprotein E4
allele (APOE-e4), while neuropathological hallmarks of AD include both intracellular pathological neurofibrils as
well as extracellular accumulation of Amyloid beta (Aß) plaques. However recent studies suggest other
pathological factors such as cerebral iron content may also play important roles and may combine with
amyloid-ß to accelerate clinical deterioration. The recent development of quantitative susceptibility mapping
(QSM) using MRI phase measurement offers a non-invasive measure of cerebral iron at high spatial resolution,
allowing in vivo assessment of local iron concentration in brain regions vulnerable to AD pathology. This
provides a great opportunity for improving our knowledge on the pathophysiological mechanism of AD related
to brain iron. A large set of susceptibility MRI data, including longitudinal follow-ups, has already been acquired
as part of the NIH funded BIOCARD study located at Johns Hopkins with extensive valuable measurement on
cognitive, clinical, genetic, and other AD biomarker data, including up to 20 years of prior cognitive testing. The
overall objective of the proposed project therefore is to analyze these data and determine the contribution of
cerebral iron load to cognitive aging and cognitive impairment related to Alzheimer’s disease (AD) in elderly
population. In the proposed project, our first aim is to determine whether local cerebral iron level is associated
with cognitive performance in cognitively normal subjects and MCI in a cross-sectional way. We will first
determine the local brain iron level using QSM analysis of the MR phase data with recently developed
automated susceptibility brain multi-atlas quantification tools. We will then test the hypothesis that increased
iron levels in certain vulnerable brain regions is significantly associated with lower cognitive performance
accounting for other known AD risk factors such as APOE-e4 genetic status, brain atrophy and cerebral Aß
load. The interaction between brain iron levels and Aß load measured by PET imaging will further be assessed
in these regions. For the second aim we will measure the cerebral iron deposition rate using the longitudinal
dataset acquired in the same cohort in brain regions where cerebral iron levels are associated with cognitive
performance as found in the first aim. We will then test the hypothesis that higher cerebral iron levels and
faster iron deposition rate in these AD vulnerable brain regions are associated prospectively with greater short-
term cognitive decline, particularly among participants with MCI, and retrospectively with more negative long-
term cognitive trajectories in the years preceding the iron measurement. If successful, we will help establish
the role of brain iron accumulation in AD on cognitive decline and its relation to other AD risk factors, which in
turn would help better understand the AD pathophysiology and potentially help establish new imaging markers.