# Alzheimer variants: Propagation of shared functional changes across cellular networks

> **NIH NIH U01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $1,625,206

## Abstract

Project Abstract
Genetic studies of Alzheimer’s disease (AD) and related-diseases (ADRD) have identified over 72 loci associated
with susceptibility. Although some of the most penetrant variants have been studied independently, the majority
of sequence variants and features are unlikely to act in isolation. In addition, the range of susceptibility loci cover
coding, epigenetic, and regulatory regions of the genome, suggesting complex relationships that cannot be
captured by large-scale transcriptomic and proteomic profiling alone. With this in mind, we systematically
interrogate combinations of variants across validated AD loci in a cell autonomous and non-autonomous manner
using a combination of molecular, epigenetic, and functional assays. This allows to create a functional network
across AD loci, and identify nodal points where the effects of individual loci interact to trigger the hallmarks of
AD pathology and clinical phenotypes. As part of this effort, we propose to establish a novel AD Locus Annotator
interface that synthesizes information about AD-associated sequence features from reference databases
encompassing existing multi-omic and clinical data, as well as new data sets that capture quantitative proteoform
and cellular functional data; these latter two data modalities have been under-characterized in AD research to
date, but are crucial to identifying cross-loci interactions. From this synthesized data analysis and portal effort,
we then establish a set of gene editing efforts to validate and extend our mechanistic understanding of multi-
locus functional networks from these AD-associated sequence features. Taken together, these analyses and
experiments allow us to link the heterogeneity of AD-associated genetic variation and clinical manifestations into
a coherent framework that link AD loci with the temporal sequence of events in AD onset and progression.

## Key facts

- **NIH application ID:** 10448247
- **Project number:** 5U01AG072572-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** PHILIP L DE JAGER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,625,206
- **Award type:** 5
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448247

## Citation

> US National Institutes of Health, RePORTER application 10448247, Alzheimer variants: Propagation of shared functional changes across cellular networks (5U01AG072572-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10448247. Licensed CC0.

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