Epidemiologic Study of Neural Reserve and Neurobiology of Aging

PROJECT SUMMARY/ABSTRACT
Extensive progress was made in the previous funding period of the Rush Memory and Aging Project (MAP). We 1)
elucidated the neuropathologic basis of cognitive decline due to Alzheimer’s disease and related disorders (ADRD),
2) discovered genomic, experiential, psychological, and medical risk factors for ADRD clinical and pathologic traits
including numerous risk factors for Alzheimer’s dementia with little to no relationship with ADRD brain pathologies,
and 3) identified numerous potential novel therapeutic targets for cognitive decline, especially targets for cognitive
decline not explained by common brain pathologies i.e., resilience. Here, the average person has average resilience
and individuals can be more or less resilient. Resilience is a high value therapeutic target because if druggable it
would offset the effects of any combination of brain pathologies.
In this funding cycle, we propose to continue to follow MAP participants and conduct autopsies, and in this cycle, to
obtain skin biopsies at autopsy to support a powerful new drug discovery program that integrates existing brain
omics data with a new human cellular model of disease, i.e., skin derived fibroblast cultures induced into neuronal
lines from persons with more or less resilience. We propose to: 1) define a robust and specific molecular signature of
resilience in the human brain; 2) identify gene targets of resilience and establish human low-resilience cell models
derived from MAP participants of known resilience; and 3) conduct drug discovery screens in the low-resilience
models to identify compounds that increase resilience. These aims are supported by compelling preliminary work.
An Exploratory Aim will continue to identify risk factors for ADRD clinical and pathologic traits leveraging the rich
resource generated from the exposure data, repeated measures, and neuropathologic traits . All aims will examine
sex as a biologic variable. A Secondary Aim will continue to share the unique and valuable resources generated by
MAP including the to-be-generated fibroblast cell lines with the scientific community.
Harnessing mechanisms of resilience to ADRD can slow down or prevent cognitive decline regardless of the
presence and complexity of common brain pathologies. Therefore, the genes and compounds identified from our
study will provide new therapeutic remedies to boost brain reserve in combating ADRD-related dementia. We believe
that the proposed continuation will have a high and sustained impact on the field of aging and dementia research.

Grant Number: 5R01AG017917-20
NIH Institute/Center: NIH
Principal Investigator: DAVID BENNETT