# Genetic interaction of PICALM and APOE in Alzheimer's disease

> **NIH NIH R03** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $165,000

## Abstract

SUMMARY
Alzheimer's disease (AD) is the most common form of dementia in the elderly, manifesting progressive
neurodegenerative conditions including amyloid plaque and neurofibrillary tangle formation, and cognitive
impairment. Genetic inheritance is estimated to determine nearly 80% of the AD cases. Besides the well-known
familial mutations in APP, PSEN1 and PSEN2 genes found in early-onset AD cases, over 30 loci or genes are
associated sporadic late-onset AD (LOAD) as indicated by recent genome-wide association studies and whole
exosome/genome sequencing projects. APOE and PICALM are among the top of the list. APOE encodes the
lipid carrier apolipoprotein E protein. Among its three major isoforms (ε2, ε3, and ε4), ε3 is the most common
isoform, ε4 is unarguably the strongest genetic risk factor for LOAD, and ε2 is the less frequent but is protective
for AD. These isoforms also differentially affect molecular and cellular events that are important for amyloid β
(Aβ) metabolism and neurodegeneration. On the other hand, PICALM encodes the phosphatidylinositol binding
clathrin assembly protein, and is confirmed by nearly all GWAS studies as a major AD-associated gene. PICALM
controls receptor internalization and subsequent intracellular trafficking of clathrin-coated vesicles. It plays key
roles in mediating brain clearance of Aβ, regulating activities of β- and γ-secretases for Aβ production, mitigating
Aβ toxicity in neurons, and promoting Tau clerance via autophagy. More interestingly, the unique genetic
interaction between APOE and PICALM in AD has been demonstrated based on population studies, as PICALM
genotypes at multiple AD-associated confer risk predominantly in ε4 carriers, and AD risk PICALM rs3851179G
allele and APOE ε4 allele synergistically affect cortex volume and working memory function in AD patients.
However, the mechanism underpinning this interaction in AD is still unknown.
Based on the PICALM's interactome and functions in maintaining cell surface protein functions, as well as our
preliminary findings showing impaired APOE lipidation and reduced level of surface ABCA1 cholesterol and
phospholipid transporter in PICALM deficient mice, we hypothesize that PICALM may facilitate APOE lipidation
and Aβ metabolism by controlling the function of ABCA1 transporter, and therefore risk PICALM rs3851179G and
APOE ε4 alleles adversely affect AD pathogenesis. To test this hypothesis, we propose to: i) determine the
cellular and molecular mechanisms of PICALM in facilitating APOE lipidation and characterize PICALM-
dependent internalization and trafficking of ABCA1 transporter (AIM 1); ii) explore the functional impact of
PICALM and APOE's synergistic interaction in vivo on neurodegenerative phenotypes (AIM 2). We expect to
gather first-hand evidence that the risk alleles of two genes synergistic influence AD pathogenesis, and establish
the molecular and cellular mechanisms of interaction between APOE and PICALM both in vitro and in vivo. Th...

## Key facts

- **NIH application ID:** 9914200
- **Project number:** 5R03AG063287-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Zhen Zhao
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $165,000
- **Award type:** 5
- **Project period:** 2019-04-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914200

## Citation

> US National Institutes of Health, RePORTER application 9914200, Genetic interaction of PICALM and APOE in Alzheimer's disease (5R03AG063287-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9914200. Licensed CC0.

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