# The Alzheimer's Disease Resiliome:  Pathway Analysis and Drug Discovery.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $660,668

## Abstract

There are no effective drugs to prevent Alzheimer’s disease (AD). We seek to prevent onset or progression of
AD by discovering and enhancing the activity of naturally occurring pathways that prevent its occurrence. This
natural resilience is significant because it is the only known manner in which Alzheimer’s appears to be
controlled. Here, we exploit the fact that a proportion of the aging population appear to remain cognitively intact
while controlling or compensating AD related Tau pathology and enjoy a relative natural resistance to cognitive
impairment or diagnosis of AD. Using whole genome sequencing (WGS) and transcriptome analysis of a
naturally AD-resilient population, we will identify novel drug-sensitive resilience associated (RA) pathways in
AD. We will implement a novel, validated technology, the Pathway Drug Network (PDN), constructed from
human gene expression data enriched in drug–pathway–gene clusters, to identify drugs that enhance RA
pathways. First round screening of the PDN-predicted single or combinations of leads will be tested in our
innovative 3D human neural cell culture models of AD, which recapitulate various pathogenic stages of AD
including Ab deposition (Ab plaque), Ab-driven tau pathology (neurofibrillary tangles (NFTs), and
neuroinflammation and neurodegeneration. Validated leads will then be scored in transgenic AD mouse
models for reduction of synaptic loss and cognitive integrity. The approach will establish the basis for a
therapeutic intervention that can prevent or reduce cognitive decline related to AD. Intellectual merit: This
project will significantly advance the understanding of neuroprotection in aging adult human brains while
providing novel insights into the relationships between control of AD related pathology and loss of cognition.
Broader impact: AD increasingly affects the aging population and there is no effective intervention. Reduction
of its incidence will be of major significance. If successful, the project will allow development of clinical
application of novel drugs or repurposed FDA approved drugs while creating a powerful new paradigm for
developing successful AD drug combinations. Aim1: Using network analytical techniques, we will generate a
molecular systems definition of RA pathways using pathways, genes and network modules from whole
genome sequencing data and literature, and post mortem brain transcriptomes that show resilient high or low
plaque/tangle, low AD symptoms, but high cognitive scores. Aim 2: Compare RA pathways within PDN to
predict drug/pathway combinations that confer resilience. A series of drug-repurposing screens will optimise
lists of ranked drugs/combinations and pathway activity. Selected combinations will be validated in multiple 3D
human neural cell culture models of AD that mimic various pathogenic stages of AD for their impact on AD
pathogenic markers. Aim 3: Validate using proxies of cognition in an AD transgenic APP mouse model. Score
for the ability to con...

## Key facts

- **NIH application ID:** 9969304
- **Project number:** 5R01AG062547-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Winston Alexander Hide
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $660,668
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969304

## Citation

> US National Institutes of Health, RePORTER application 9969304, The Alzheimer's Disease Resiliome:  Pathway Analysis and Drug Discovery. (5R01AG062547-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969304. Licensed CC0.

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