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

> **NIH NIH U01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $432,310

## 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 multilocus 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:** 11126418
- **Project number:** 3U01AG072572-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** PHILIP L DE JAGER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $432,310
- **Award type:** 3
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11126418

## Citation

> US National Institutes of Health, RePORTER application 11126418, Alzheimer variants: Propagation of shared functional changes across cellular networks (3U01AG072572-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11126418. Licensed CC0.

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