Principal Investigator/Program Director (Last, First, Middle): Morris, Martha Clare
This R01 application, entitled “Epidemiological Neuropathologic Study of Metallomics and Alzheimer's
Disease” is a new submission in response to PAR-15-356. By the year 2050 it is projected that there will
be 13.5 million Americans with AD at a cost of $1.1 trillion. Recent large-scale phase III clinical trials of drugs
targeting known pathways involved in AD have either failed to benefit patients, or indicated very limited
efficacy. Whereas beta amyloid (Aß) may be a principal driver of the disease, multiple failed clinical trials of
drugs targeting this peptide suggest that Aß is a poor therapeutic target for AD. Iron accumulates in the
affected brain regions in AD, and has the potential to drive disease progression by causing oxidative stress
and the aggregation of Aß and tau, and is thus an alternate therapeutic target. In previous studies we showed
that the iron burden of the brain (as reflected in CSF ferritin levels) has an effect on multiple longitudinal
outcomes of AD comparable in magnitude to more established factors in the disease: tau and Aß. We have
preliminary data showing a strong positive association between brain iron levels and neurofibrillary tangle
pathology, particularly in APOE-e4 carriers. There has not been a systematic, well powered, and detailed
exploration of brain iron levels in AD. Here, we propose to use a large, well-characterized post mortem cohort
study, the Rush Memory and Aging Project, to investigate brain iron concentrations in AD of 680 autopsied
brains using advanced techniques. We will investigate the impact of the iron load of the brain on AD
neuropathology and cognitive clinical history; investigate potential causes of iron accumulation in AD including
diet, and genetic factors; and explore neurochemical mechanisms of iron elevation using advanced proteomics
and metalloproteomics. This foundational study has the potential to (1) establish whether iron concentrations
are related to the disease, (2) validate iron as a therapeutic target for AD, (3) discover new molecular targets
for lowering iron, (4) identify whether diet influences brain iron levels and AD risk, and (6) determine whether
genetic factors, including APOE allele variation, impacts on iron in AD.
PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page