# Defining high- and low-risk APOE ε4 haplotypes for Alzheimer’s disease

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2021 · —

## Abstract

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD),
with an impact orders of magnitude larger than all other AD-linked genes combined. In the past, mainstream
research of APOE in AD has focused on structural and functional differences among apoE protein isoforms.
Yet, despite the broad and valuable hypotheses that work has generated, the exact mechanism by which
APOE contributes to AD remains elusive, thus hindering development of precise APOE-based therapeutic
strategies. In order to develop more effective approaches to treat and ultimately prevent AD, it will require
outside the box thinking and research efforts aimed at identifying the underlying mechanisms of APOE’s role in
AD. Several lines of emerging evidence suggest the presence of other AD-risk loci in close proximity to APOE.
For example, recent genome-wide association studies (GWAS) have consistently identified APOE and its
adjacent regions to be strongly associated with AD. In our preliminary study, we analyzed the genetic
association of an extended APOE region using Alzheimer’s Disease Genetics Consortium (ADGC) GWAS
data. We observed that multiple single nucleotide polymorphisms (SNPs) all carry strong AD association
signals independent of the APOE ε4 allele. This region consists of 11 critical SNPs that span four genes (i.e.,
PVRL2, TOMM40, APOE, and APOC1), most of which have AD-specific mRNA expression in postmortem
brain. From this evidence and observations, we hypothesize that multiple genes and loci in the extended
APOE region contribute to AD risk, and genetic variants of these loci compose distinct haplotypes that
differentially regulate local gene expression to modify the AD risk. This concept forms the foundation of the
current proposed study. We have designed a research plan, and our short-term goals are to identify APOE-ε4
independent genetic loci associated with AD, and to precisely define how genetic variability in this extended
APOE region contributes to AD risk. We will first construct molecular haplotypes across this region and
determine their genetic association with AD risk. We will then investigate how these haplotype variants
correlate to gene expression and explore any underlying regulatory mechanisms. Our long-term goal is to use
this knowledge to develop more precise APOE locus-based prediction, prevention, and/or therapeutic
strategies for AD.

## Key facts

- **NIH application ID:** 9884401
- **Project number:** 1I01BX004823-01
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** CHANG-EN YU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884401

## Citation

> US National Institutes of Health, RePORTER application 9884401, Defining high- and low-risk APOE ε4 haplotypes for Alzheimer’s disease (1I01BX004823-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9884401. Licensed CC0.

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