Genetic and Neuropathologic Underpinnings of Sex Differences in Lewy Body Dementias

PROJECT SUMMARY
Sex differences are commonly reported in Lewy body dementia, although the reasons are unknown.
Phenotypic differences can be described by differences in the pathology and can be associated with
differences in genetic risk loci. We hypothesize that Alzheimer's disease-related genetic risk factors will be
associated with higher dementia risk in women with Lewy body dementia, given the higher likelihood of
Alzheimer's co-pathology in women. However, even for women with pure Lewy body pathology,
Alzheimer's phenotype is more common than Lewy body dementia phenotype, indicating sex differences
for clinicopathologic correlations. This may be due to differences in regional pathology burden for men and
women. Specific regional Lewy body and Alzheimer's pathology burden have been associated with different
symptoms; and we hypothesize that men will have more neocortical Lewy body burden and women will
have more pathology burden in the medial temporal lobe given the more common Alzheimer's phenotype in
women. As Alzheimer's disease is the most common misdiagnosis for patients with Lewy body dementia,
we will also develop sex-specific models with clinical and genetic variables to clinically differentiate Lewy
body and Alzheimer's pathology. These findings will improve our understanding of the etiopathogenesis of
Lewy body dementia, assist with patient selection for future clinical trials in both Lewy body dementia and
Alzheimer's disease, and provide targets for precision medicine in these neurodegenerative dementias.
The candidate is an Assistant Project Scientist (a mentored position) at the University of California San
Diego. She has an MD and a PhD with prior training in neurodegenerative disorders, neuropsychology, and
neuroimaging. She has a history of productivity, having conducted translational and clinical research in
movement disorders, recently focusing on sex differences in Parkinsonian disorders. She is committed to a
research career in translational research and proposes a comprehensive five-year plan of research and
training to acquire skills in 1) genetic and genomic analysis, 2) interpreting neuropathological data, 3)
performing statistical analyses with big data. During the award period, Dr. Bayram will build collaborative
relationships with experts in the field of genetics, neuropathology, and bioinformatics to support her work as
an independent researcher. This award will also support Dr. Bayram's professional development including
training for grantsmanship, leadership, and administrative skills. Dr. Bayram will meet her goals under the
guidance of a mentoring team including Dr. Irene Litvan (primary mentor), a world-renowned expert in
cognitive decline in Parkinsonian disorders, Dr. Sonja Scholz (co-mentor, neurologist-neurogeneticist at
NINDS), Dr. Ali Torkamani (bioinformatics mentor), Dr. David Salmon (neuropsychology mentor), Dr.
Dennis Dickson (advisor, pathologist), Dr. Owen Ross (advisor, geneticist) and Dr. Abraham Palmer
(advisor, geneticist), all of whom are well-established and NIH-funded researchers.

Grant Number: 5R00AG073453-04
NIH Institute/Center: NIH
Principal Investigator: ECE BAYRAM