# Elucidate the roles of Alzheimer's disease risk genes and variants in gene expression and AD-related phenotypes

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $3,716,281

## Abstract

Project Summary/Abstract
AD is an age-related neurodegenerative disorder affecting 10% of the population over 65. The genetics of Late-
onset AD (LOAD) is complex. Multiple common variants usually influence LOAD with smaller effect sizes.
Whether and how these predicted AD risk genes contribute to AD pathogenesis and which variant affect their
expression remain, for the most part, to be characterized. The overarching goal of the proposed study is to
provide a comprehensive annotation of roles for AD risk genes and determine AD casual variants contribute to
AD via modulating AD-risk gene expression. We will: (1) determine and benchmark the biological consequences
of putative AD risk genes identified by genetic analysis using CRISPRi and single-cell RNA-seq in iPSC-derived
excitatory neurons, hippocampal dentate granule cells, and microglia. We will also follow up using functional
assays in cells and organoids for AD-related phenotypes, (2) characterize enhancers and AD-associated variants
for AD risk genes in iPSC-derived hippocampal DG neurons and hippocampal organoids, (3) elucidate the roles
of enhancers and AD variants in iPSC-derived excitatory neurons, microglia, and cerebral organoids with
microglia. The proposed work will provide a comprehensive annotation of AD risk genes and demystify AD-
causal variants affecting gene expression networks and cellular functions related to AD pathogenesis. The
success of our proposal will be an essential step towards better risk prediction and new therapeutic targets in
AD.

## Key facts

- **NIH application ID:** 10538968
- **Project number:** 1RF1AG079557-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Li Gan
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,716,281
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538968

## Citation

> US National Institutes of Health, RePORTER application 10538968, Elucidate the roles of Alzheimer's disease risk genes and variants in gene expression and AD-related phenotypes (1RF1AG079557-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10538968. Licensed CC0.

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