# Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models

> **NIH NIH U01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $1,629,020

## Abstract

SUMMARY
Alzheimer’s Disease (AD) is projected to affect 13 million people in the US by 2050 and remains neither
curable nor preventable. Following remarkable recent progress, the genomic architecture of AD and related
dementias (ADRD) is coming into focus. Similar to other common and genetically complex disorders, AD is
characterized by substantial locus heterogeneity and polygenic susceptibility: risk or protective alleles are
being identified in many distinct genes, and in most individuals, a subset of common and rare variants likely
interact to trigger neurodegeneration. The critical next steps include confirmation of the responsible genes,
understanding the functional impact of disease-associated variants, elaboration of the relevant cell types and
pathways, and determining how polygenic interactions mediate disease risk. We propose an integrated
computational and tiered experimental validation strategy to accelerate AD functional genomics, building on
advances from the AD Sequencing Project (ADSP) and leveraging powerful technologies available in the fruit
fly, Drosophila melanogaster. First (AIM 1), leveraging infrastructure developed for the Clinical Genome
Resource and ENCODE projects, we will integrate ADSP results with other human data, including brain
transcriptome and epigenome profiles, prioritizing genes and variants for experimental follow-up. Next (AIM 2),
using high-throughput Drosophila screening, we will systematically manipulate 2,000 conserved, candidate AD
genes in vivo to pinpoint causal modulators of age-dependent neurodegeneration, including interactions with
Tau, Aß, and other pathologic triggers. Third (AIM 3), for a subset of 200 prioritized gene candidates, we will
generate customized Drosophila strains and characterize cell-type expression and loss-of-function phenotypes.
Lastly (AIM 4), for 50 high-priority targets, we will experimentally probe mechanisms in-depth, including testing
of cell-type specific requirements (neurons vs. glia) and examining gene-gene interactions that define relevant
pathways. We will broadly share all project data and resources with the research community (AIM 5). Our
integrative, tiered, cross-species strategy promises rapid functional annotation of ADSP targets using powerful,
in vivo assays in the aging nervous system of Drosophila, and is ideally suited for reciprocal cross-validation in
complementary mammalian preclinical models. On a scale and timeframe not currently possible in other model
systems, our innovative experimental strategy will transcend barriers to translation of human genetic
discoveries and catalyze breakthroughs in our understanding AD pathobiology.

## Key facts

- **NIH application ID:** 10215922
- **Project number:** 1U01AG072439-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** HUGO J BELLEN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,629,020
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215922

## Citation

> US National Institutes of Health, RePORTER application 10215922, Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models (1U01AG072439-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215922. Licensed CC0.

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