Risk Factors, Pathology, and Clinical Expressions of AD

ABSTRACT
Over the past project periods we tracked the biological basis of cognitive decline and dementia to understand
the heterogeneous contributions of a dozen brain pathologies to individuals in the Religious Orders Study and
Rush Memory and Aging Project (ROSMAP). We identified numerous genomic, medical, experiential, and
psychological factors associated with cognitive decline and incident Alzheimer’s dementia, and also
neurobiologic pathways linking some of these factors to Alzheimer’s disease (AD) and to related dementias. In
the most recent funding period, to understand the biological basis of risk factors, we analyzed multi-region
multi-omic data to identify novel and potentially high value therapeutic targets for the treatment and prevention
of AD and related dementias. The computational biology target nominations were validated with targeted
proteomics. All data are well-organized and shared publically with stakeholders around the globe.
The overall goal of the proposed continuation is to identify additional protein targets, and their splice
isoforms and post-translational modifications (PTMs) that drive AD related traits and can serve as
novel therapeutic targets. We focus specifically on the hippocampus and entorhinal cortex, a region that is a
key hub in the neurodegenerative disease network. Further, several neurodegenerative disease pathologies
including tau tangles, TDP-43, Lewy bodies, and hippocampal sclerosis, are far more common in these regions
relative to the neocortical regions with existing omic data.
Aim 1 will generate bulk and single cell RNAseq and deep tandem mass tag (TMT) proteomics which can now
generate upwards of 10,000 unique proteins making it virtually genome-wide; it will use these data to identify
cell type-specific molecular systems, i.e., dozens to hundreds of coexpressed genes and proteins. Aim 2 will
identify the specific molecular systems that drive AD related traits; further, through integration of all omic data
from all regions it will identify key drivers of these systems. This will nominate genes and proteins that could
serve as therapeutic targets. Aim 3 will perform top-down proteomics to identify splice isoforms, proteolytic
fragments, and post-translational modifications of select high value proteins. Secondary aims will continue to
explore the biologic pathways linking risk factors to AD related traits which has been the main deliverable of
this grant since its inception; it will also share the newly generated data with the wider AD research community.
The proposal will deliver high value therapeutic targets which will be passed to the Accelerated Medicines
Partnership-AD (AMP-AD) consortium for further study. Thus, the identification of these proteins will have a
high and sustained impact on the field of aging and dementia.

Grant Number: 5R01AG015819-21
NIH Institute/Center: NIH
Principal Investigator: DAVID BENNETT