# Alzheimer's Disease Genetic Risk and Microglial Innate Immune Memory

> **NIH NIH F30** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $46,060

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by cognitive decline and
an accumulation of amyloid pathology. A strong genetically-driven innate immune component is thought to play
a pathogenic role in AD, implicating a central role for microglial dysfunction. Microglia are long-lived resident
innate immune cells in the central nervous system. Activation of their immune and metabolic pathways lead to
innate immune memory (IIM), a functional reprogramming process in which the response to an initial stimulus
shapes long-lasting epigenetic modifications which inform the response to subsequent stimuli. IIM may result in
enhanced activation (training) or suppression (tolerance) based on the identity of the initial inflammatory
stimulus. IIM has been shown to alter pathology in AD mouse models, as a consequence of a sustained alteration
in microglial functioning. Several common AD risk variants, including CD33, converge to suppress microglial
activation, by decreasing inflammatory signaling or increasing its inhibition. Accordingly, my overall hypothesis
is that altered microglial IIM as a result of suppressive genetic AD risk variants is a critical mechanism underlying
the observed microglial dysfunction in AD. More specifically, I hypothesize that the suppressive CD33 AD-risk
variant will reduce epigenetic and metabolic rewiring that occurs upon cellular activation, impairing microglial
IIM. This sustained alteration of responsiveness at the epigenetic level may contribute to microglial failure as a
pathogenic mechanism in AD. To address these hypotheses, I propose to examine the mechanisms of human
microglial IIM in response to AD associated inflammatory stimuli, including amyloid and tau, and the effect of the
CD33 risk variant on this imprinting process. In Aim 1, I will investigate human microglial IIM phenotypic
outcomes in HMC3s (a human microglial cell line) edited with CRISPR to carry the CD33 AD risk allele. I will test
whether a range of AD-associated inflammatory stimuli produce trained or tolerized IIM responses, and how
CD33 genotype affects these outcomes. In Aim 2, I will investigate the epigenetic and metabolic mechanisms
underlying IIM in HMC3s carrying the CD33 risk or protective alleles. These studies will provide mechanistic
insight into longitudinal interactions between microglia and local brain pathology, as well as how the CD33 risk
variant mediates microglial dysfunction and ultimately AD susceptibility. Importantly, they will also advance our
understanding of IIM in human microglia, of which little is known, and the IIM phenotypes they adopt in response
to AD pathologies. Their successful conclusion may thus open novel avenues for the development of potential
therapeutics to target microglial dysregulation in AD, and to ultimately improve patient outcomes.

## Key facts

- **NIH application ID:** 10314478
- **Project number:** 1F30AG074618-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Zena Chatila
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,060
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314478

## Citation

> US National Institutes of Health, RePORTER application 10314478, Alzheimer's Disease Genetic Risk and Microglial Innate Immune Memory (1F30AG074618-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10314478. Licensed CC0.

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