# Biology and pathobiology of apoE in aging and Alzheimer's disease

> **NIH NIH U19** · MAYO CLINIC  JACKSONVILLE · 2021 · $6,820,292

## Abstract

PROJECT SUMMARY (APOE U19: OVERALL)
The overarching goal of this U19 project is to comprehensively understand the biology and pathobiology of
apolipoprotein E (apoE) in aging and Alzheimer’s disease (AD) to inform therapeutic strategies. The ε4 allele of
the APOE gene (APOE4) is the strongest genetic risk factor for AD impacting 50-70% of all AD patients, while
the ε2 allele is protective compared to the common ε3 allele. APOE4 is also a strong risk factor for age-related
cognitive decline and vascular cognitive impairment. To integrate existing knowledge and address critical gaps,
we propose a unified ApoE Cascade Hypothesis that the structural differences and related biochemical
properties among the three apoE isoforms initiate their differential effects on a cascade of events at the cellular
and systems levels ultimately impacting aging-related pathogenic conditions including AD. Towards this, we
have assembled a multi-disciplinary team to synergize expertise and resources across multiple institutions. By
integrating five interactive Projects and seven robust Cores, we will create a nexus for apoE-related aging
research, sharing the knowledge, expertise and resources with the broader scientific community. Project 1 will
work closely with Core B to address the structural and biochemical properties of the three apoE isoforms to
generate insights for functional outcomes. Projects 2, 3 and 4 will interactively study how apoE isoforms
expressed in astrocytes, microglia, or vascular mural cells impact lipid metabolism, glial and vascular functions,
AD-related pathologies, and cellular and molecular pathways using conditional mouse models and systems-
based approaches. These studies will generate cell type-specific apoE/lipoprotein particles that will be
collected through in vivo microdialysis for structural and biochemical studies. Project 5 will carry out genomic
and genetic analyses to identify modifiers of APOE-related age at onset of AD. Studies in Projects 2-5 will be
interactively supplemented by neuropathological studies using postmortem brains from healthy aging studies
or with AD pathologies (Core C), biomarker studies using both human and mouse biospecimens (Core D), and
functional studies using human iPSC-derived cellular and organoid models (Core E). This U19 proposal is
supported by a comprehensive Multi-Omics Core (Core F) for centralized proteomics, lipidomics, and
metabolomics studies on various animal and iPSC models, as well as human postmortem brains and fluid
biospecimens. The Bioinformatics, Biostatistics, and Data Management Core (Core G) will provide critical
supports for analyzing large datasets including those from single-cell RNA-seq and biostatistics supports to
ensure scientific rigor. Core G will also work closely with the Administrative Core (Core A) to maintain an ApoE
Web Portal designated as EPAAD where knowledge, resources, and data will be shared with the scientific
community. Core A will also organize annual ApoE ...

## Key facts

- **NIH application ID:** 10087377
- **Project number:** 1U19AG069701-01
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** GUOJUN BU
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $6,820,292
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087377

## Citation

> US National Institutes of Health, RePORTER application 10087377, Biology and pathobiology of apoE in aging and Alzheimer's disease (1U19AG069701-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10087377. Licensed CC0.

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