# Modeling the impact of regulatory and splicing variants on cellular function in Alzheimer's disease

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $2,360,820

## Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive 
cognitive decline and dementia. Despite more than fifty years of research, no cures exist and the 
standard of treatment remains unsatisfactory. Genome wide association studies (GWAS) 
indicate that AD risk reflects both highly penetrant rare variants as well as common 
single nucleotide polymorphisms with small effect sizes. By overlapping GWAS and post-mortem 
and myeloid cell expression analyses, we have identified common variants with expression and 
splicing quantitative trait loci that may contribute to altered gene expression or alternative 
splicing; however, demonstrating which risk loci are the causal contributors to disease risk 
remains an intractable problem. Here, we will apply statistical approaches to prioritize putative 
causal variants in AD-associated loci by incorporating expanded AD GWAS functional annotations, 
single cell chromatin profiles and histone modification and microglia gene expression datasets. We 
will then apply a human induced pluripotent stem cell (hiPSC)-based approach to manipulate 
the genotype of prioritized putative causal AD risk variants that alter gene expression 
or alternative splicing of mRNAs, focusing largely on genes implicated in phagocytosis 
and lysosomal-autophagy function. Through isogenic comparisons of neurons, microglia, and 
astrocytes, we propose to examine the molecular and functional effects of perturbing five putative 
causal SNPs separately testing their cell autonomous and non-cell autonomous impact on cellular 
function. Our hope is that this work may identify novel therapeutic points of intervention in order 
to prevent or slow disease course in individuals with AD. This project will have a large overall 
impact by providing a mechanistic interpretation of genetic variants associated
with AD susceptibility.

## Key facts

- **NIH application ID:** 10123357
- **Project number:** 1RF1AG065926-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kristen Jennifer Brennand
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,360,820
- **Award type:** 1
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123357

## Citation

> US National Institutes of Health, RePORTER application 10123357, Modeling the impact of regulatory and splicing variants on cellular function in Alzheimer's disease (1RF1AG065926-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123357. Licensed CC0.

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