# Define the effect of CLU SNP on the risk to Alzheimer's disease

> **NIH NIH RF1** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2022 · $1,942,962

## Abstract

Project Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and there is no cure for this
disease. The molecular and cellular mechanisms underlying AD pathogenesis remains to be elucidated to
develop effective therapies for this disease. Many mouse models have been generated for AD research and
these models provide important insights to aid our understanding of the pathological basis of the disease.
However, because there are significant species differences between mouse and human neural cells, establishing
human disease modeling platforms is needed to complement studies in animal models to better understand AD.
 Human induced pluripotent stem cells (hiPSCs) have been widely used for disease modeling since the
development of the iPSC technology. hiPSCs have been used to model various aspects of AD. Because hiPSCs
and their derivatives have been considered phenotypically young, hiPSC-derived cells have been used to model
early events of AD. Direct reprogramming is another type of reprogramming that converts one type of somatic
cells into another without going through the iPSC stage that involves extensive epigenetic modifications, thus
enabling generation of human cells that possess key elements of cellular aging. Therefore, directly
reprogrammed cells derived from patient somatic cells would allow us to model age-related pathologies of AD.
 ApoE4 is the strongest and the C allele of the CLU rs11136000 SNP is the third strongest genetic risk factor
for AD. The objective of this proposal is to define the effect of the CLU rs11136000 SNP alone or together with
ApoE4 on the risk to AD and uncover molecular and cellular mechanisms underlying the effect, using human
cellular models generated from hiPSCs or through direct reprogramming. We will use gene-edited isogenic cells
to define the effect of CLU SNP in combination with ApoE isoform. In addition, because hiPSC-derived cells and
directly reprogrammed cells derived from the same donors have the same genetic background but different
cellular aging status, they represent isogenic cellular platforms that will enable us to specifically study the effect
of cellular aging. These isogenic models will allow us to recapitulate age-associated phenotypes and uncover
novel pathological mechanisms underlying AD. Because both CLU and ApoE are highly expressed in astrocytes,
we propose to define the effect of the CLU SNP alone or together with ApoE using astrocytes. We hypothesize
that CLU modulates AD pathologies in an ApoE isoform- and age-dependent manner. Therefore, we propose
following Specific Aims: Aim 1: To derive astrocytes with different APOE/CLU genotypes and cellular aging
status from hiPSCs or through direct reprogramming. Aim 2: To define the effect of APOE and CLU variants on
AD pathogenesis using astrocyte-neuron or astrocyte-OPC co-cultures. Aim 3: To determine the relationship of
APOE/CLU genotypes and aging with gene expression change in human brains. The proposed...

## Key facts

- **NIH application ID:** 10526184
- **Project number:** 1RF1AG079307-01
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** YANHONG SHI
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,942,962
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526184

## Citation

> US National Institutes of Health, RePORTER application 10526184, Define the effect of CLU SNP on the risk to Alzheimer's disease (1RF1AG079307-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10526184. Licensed CC0.

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