# Combinatorial Actions of Genetic Variants and Gender Bias of Alzherimer's Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $1,523,715

## Abstract

PROJECT ABSTRACT
Alzheimer’s disease (AD) is conventionally characterized by specific neuropathological features, including the
appearance of extracellular amyloid deposits and the accumulation of intracellular neurofibrillary tangles. While
several gene mutations are clearly associated with early onset Alzheimer’s disease, the large number of
individuals exhibiting delayed onset, aging-associated AD, are likely to harbor many alterations in linked modifier
genes that predispose to AD susceptibility. Genetic and genome wide association studies (GWAS) have
identified numerous genes and risk alleles that indicate both cell autonomous and non-cell autonomous
mechanisms contributing to loss of neurons and cognitive decline. In this regard, the majority of risk variants
identified by GWAS reside in non-coding regions of the genome, implying that they act in part to alter gene
expression. This proposal responds to the RFA indicating a particular need for approaches designed to delineate
the transcriptional and cellular consequences of combinations of SNPs in the risk alleles by generating new cell
line reagents to help unravel the question of the causative SNPs and their target genes in specific neurons
derived from iPS cells of AD individuals. There are two features of sporadic AD that require molecular
explanation- the potential role of aging in AD susceptibility, and the striking gender disparity, with the incidence
of AD being exaggerated in females. These issues can only now be addressed based on new technologies and
the availability of patient-derived samples. Our proposed research plan takes advantage of the invaluable
samples stored at the brain bank of the Shiley-Marcos Alzheimer's Disease Research Center (ADRC) at UCSD,
and the iPSC-derived neurons (Salk). This approach will interrogate the effects of different genetic variants with
other risk factors (e.g. age, sex), and assess their effects on cell type-specific enhancer landscapes. By merging
these data, we can begin to identify the potential causative SNPs that result in altered function of cell-type specific
enhancers. We propose using a high throughput 4C screening approach (UMI-4C), and Hi-ChIP, to identify the
most likely causative, enhancer-associated SNPs for functionally-implicated coding target genes. Exploiting the
power of contemporary gene editing approaches in control or patient-derived iPS cells to specific neuronal cell
types, and to astroglia, we can assess the transcriptional phenotypes and functional behaviors of neurons
harboring different combinations of risk alleles, both in the isolated cell lines alone and in combination with
coculture experiments with astroglia and microglia, as effects of these SNPs may be manifest only with
astroglial:neuronal interactions. Together these studies will use powerful contemporary global genomic
approaches to determine the coding transcriptional targets of several of the most significant SNPs in enhancers,
and the link to roles of est...

## Key facts

- **NIH application ID:** 9948563
- **Project number:** 5R01AG057706-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** FRED H GAGE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,523,715
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948563

## Citation

> US National Institutes of Health, RePORTER application 9948563, Combinatorial Actions of Genetic Variants and Gender Bias of Alzherimer's Disease (5R01AG057706-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948563. Licensed CC0.

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