# Trem2-APOE Pathway in Alzheimer's Disease: Exploring the differential effects of R47H on the APOE3 and APOE4 backgrounds in a tauopathy model

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $20,862

## Abstract

Project Summary
Alzheimer’s disease (AD) is one of the most common forms of dementia, affecting one in ten people over the
age of 65 and nearly half of people over the age of 85. AD is currently untreatable, posing a significant health
concern. Many attempted treatments for AD target amyloid-beta (Ab) plaques, but these treatments have all
failed in clinical trials1,2. Emerging evidence shows that tau pathology may play a causal role in the development
of AD. Inflammation prompted by microglia may precede the spread of pathogenic tau3-6, and most AD risk genes
are found in microglia, supporting a significant role for inflammation in disease7,8. Inflammation requires
metabolic reprogramming to provide the energy and substrates needed for activation9,10, and mitochondrial
dysfunction could contribute to aberrant inflammatory responses in AD11. The APOE4 risk allele along with the
R47H variant of the microglial Trem2 receptor both display large effect sizes in increasing AD risk. APOE4 is
found in approximately 20% of the population, whereas the R47H mutation is much rarer, representing less than
1% of the population12. The APOE3 allele is considered neutral to disease risk and is often used as a control
comparison in experiments. APOE is a known ligand of the Trem2 receptor, and Trem2 activation robustly
increases microglial APOE expression, as well as affecting cellular metabolism and inflammation. Activation of
the microglial Trem2-APOE pathway is associated with heightened inflammation13,14. However, the mechanistic
underpinnings of the pathway are not well understood, and there has been little research on the interactions
between risk variants R47H and APOE4. My preliminary data indicates that R47H/+ has a remarkable differential
effect on the APOE3 background compared to the APOE4 background, such that R47H with APOE3 (R47H-E3)
has heightened inflammation in response to tau and increased mitochondrial respiration, but R47H with APOE4
(R47H-E4) has low inflammatory response and decreased mitochondrial function. This differential response is
accompanied by enhanced AKT activation in R47H-E3 but reduced AKT activation in R47H-E4, suggesting
potential mechanistic involvement in these phenotypes. I hypothesize that alterations in AKT signaling drive the
differential effects of R47H on mitochondrial respiration and inflammation in the E3 vs. E4 background. In this
proposal, I aim to further elucidate the interactions of R47H with different APOE genotypes to affect microglial
metabolism and inflammation, both in vitro using a primary microglia model and in vivo using a tauopathy mouse
model. I will then explore the potential mechanistic involvement of AKT in this pathway using AKT inhibition.
These studies will provide a better understanding of the function and mechanisms of the disease-implicated
Trem2-APOE pathway in microglia, providing novel targets for the treatment of AD.

## Key facts

- **NIH application ID:** 10906231
- **Project number:** 5F31AG079560-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gillian Kirova Carling
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $20,862
- **Award type:** 5
- **Project period:** 2022-08-18 → 2024-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906231

## Citation

> US National Institutes of Health, RePORTER application 10906231, Trem2-APOE Pathway in Alzheimer's Disease: Exploring the differential effects of R47H on the APOE3 and APOE4 backgrounds in a tauopathy model (5F31AG079560-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10906231. Licensed CC0.

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