NCT04840979 - Genetic Variants Affecting Microglial Activation in AD

Overview

NCT04840979: Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease With 11C-ER176 is a Phase 2 clinical trial conducted at Columbia University in New York, New York. The study aims to identify genetic variants that influence microglial activation as measured by TSPO (Translocator Protein) PET imaging using the radiotracer [^11C]ER176. This represents a critical integration of genetics and molecular imaging to understand the role of neuroinflammation in Alzheimer's disease pathogenesis.

The trial is actively recruiting participants and is expected to complete by December 2026. With an enrollment target of 250 participants, it is one of the largest studies systematically examining genetic determinants of microglial activation in AD.

Study Design

Rationale

Microglial activation is a hallmark of Alzheimer's disease neuropathology, represents a key component of the [neuroinflammation pathway](/mechanisms/neuroinflammation-ad). However, the genetic factors that regulate individual variability in microglial activation remain poorly understood. This study addresses this gap by:

Genome-wide association approach: Identifying novel genetic variants associated with TSPO binding

Functional validation: Confirming that associated variants have biological effects on microglial function

Personalized medicine: Laying groundwork for genetically-targeted anti-inflammatory therapies

Population

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Overview

NCT04840979: Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease With 11C-ER176 is a Phase 2 clinical trial conducted at Columbia University in New York, New York. The study aims to identify genetic variants that influence microglial activation as measured by TSPO (Translocator Protein) PET imaging using the radiotracer [^11C]ER176. This represents a critical integration of genetics and molecular imaging to understand the role of neuroinflammation in Alzheimer's disease pathogenesis.

The trial is actively recruiting participants and is expected to complete by December 2026. With an enrollment target of 250 participants, it is one of the largest studies systematically examining genetic determinants of microglial activation in AD.

Study Design

Rationale

Microglial activation is a hallmark of Alzheimer's disease neuropathology, represents a key component of the [neuroinflammation pathway](/mechanisms/neuroinflammation-ad). However, the genetic factors that regulate individual variability in microglial activation remain poorly understood. This study addresses this gap by:

Genome-wide association approach: Identifying novel genetic variants associated with TSPO binding

Functional validation: Confirming that associated variants have biological effects on microglial function

Personalized medicine: Laying groundwork for genetically-targeted anti-inflammatory therapies

Population

The study enrolls:

• Alzheimer's disease patients: Clinically diagnosed AD (n≈150)
• Cognitive controls: Normal cognition elderly (n≈100)

Inclusion criteria include:

• Age 55-85 years
• Clinical diagnosis of probable AD or healthy controls
• Ability to undergo PET scanning
• Willingness to provide DNA for genetic analysis

Exclusion criteria include:

• Significant neurological conditions other than AD
• Contraindications to PET imaging
• Inability to provide informed consent

Imaging Protocol

The study uses [^11C]ER176, a third-generation TSPO PET tracer developed to address limitations of earlier tracers affected by the rs6971 polymorphism. ER176 provides:

• Improved signal-to-noise: Higher specific binding compared to [^11C]PBR28
• Reduced polymorphism sensitivity: Less affected by the rs6971 variant
• Optimal kinetics: Suitable for 60-90 minute dynamic imaging

Imaging acquisition:

Dynamic PET: 60-90 minutes post-injection

MR-based attenuation correction: Structural MRI for partial volume correction

Blood sampling: Arterial input function measurement

Standardized uptake value ratio (SUVR): Cerebellar reference region

Genetic Analysis

The study employs a two-phase design:

Phase 1: Discovery

• Genome-wide association study (GWAS) in discovery cohort
• Identify variants associated with TSPO binding
• Bioinformatics functional annotation

Phase 2: Validation

• Test identified variants in independent cohort
• Functional validation in cellular models
• Integration with gene expression data

Genetic Variants Under Investigation

Primary Variant of Interest: rs2997325

The study focuses on chromosome 1 variant rs2997325, which has been associated with TSPO binding in prior studies. This variant:

• Location: Chromosome 1q21.3
• Gene context: Near inflammatory gene cluster
• Allele frequency: ~30% minor allele frequency in Europeans
• Effect: Alters microglial TSPO expression

Hypothesized Mechanism

flowchart TD
A["Genetic variant<br/>rs2997325"] --> B{"Transcriptional<br/>regulation"}
B -->|"increased expression"| C["Higher TSPO<br/>protein"]
B -->|"decreased expression"| D["Lower TSPO<br/>protein"]
C --> E["Enhanced 11C-ER176<br/>PET signal"]
D --> F["Reduced 11C-ER176<br/>PET signal"]
E --> G["Microglial<br/>activation"]
F --> G
G --> H["Neuroinflammation<br/>in AD"]

The variant likely affects:

Transcription factor binding: Alters promoter activity

mRNA stability: Changes transcript half-life

Chromatin accessibility: Modifies enhancer function

Broader GWAS Findings

In addition to rs2997325, the study is expected to identify additional variants in:

| Gene/Region | Biological Pathway | Hypothesized Effect |
|------------|---------------|-----------------|
| TSPO gene | TSPO expression | Direct binding regulation |
| Inflammatory genes | Cytokine signaling | Microglial activation |
| Myeloid genes | Microglial function | Cell-specific effects |
| Mitochondrial genes | Energy metabolism | Cell state changes |

Outcomes

Primary Outcomes

Correlation between rs2997325 and TSPO binding

• Measure: Pearson correlation coefficient
• Expected: r > 0.3, p < 0.001

Number of variants discovered in GWAS

• Threshold: genome-wide significance (p < 5 × 10^-8)
• Expected: 5-20 novel variants

Secondary Outcomes

• Heritability of TSPO binding: Estimate narrow-sense heritability
• Pleiotropy analysis: Overlap with other inflammatory diseases
• Gene-environment interaction: Effect of age, sex, APOE status

Scientific Significance

Understanding AD Pathogenesis

This study will advance understanding of AD through:

Genetic architecture of neuroinflammation: Identifying variants that modulate microglial activation

Mechanistic insights: Linking genetic variation to biological function

Therapeutic target identification: Novel targets for anti-inflammatory therapy

Clinical Applications

Findings will enable:

Patient stratification: Identifying patients with high neuroinflammatory burden

Personalized treatment: Genotype-guided therapy selection

Clinical trial enrichment: Selecting patients most likely to respond to immunomodulatory treatments

Comparison with Other TSPO PET Studies

| Study | Tracer | Focus | Participants |
|-------|-------|-------|------------|
| NCT04840979 | [^11C]ER176 | Genetics | 250 AD + controls |
| ADNI | [^11C]PBR28 | Biomarker | 100+ AD |
| AMP-AD | [^18F]GE-180 | Treatment | Various |

ER176 offers advantages:

• Reduced sensitivity to rs6971 polymorphism
• Improved quantification
• Enhanced specific binding

Related Mechanisms

This trial intersects with several key NeuroWiki mechanisms:

• [TSPO PET imaging for neuroinflammation](/mechanisms/tspo-pet-imaging-neuroinflammation) — The imaging modality used in this study
• [Neuroinflammation in Alzheimer's disease](/mechanisms/neuroinflammation-ad) — The pathway under investigation
• [Microglial activation mechanism](/mechanisms/microglia-activation) — The cellular process being genetically profiled
• [TREM2 microglial pathway](/mechanisms/trem2-microglial-pathway) — Key AD microglial gene
• [Disease-associated microglia (DAM)](/mechanisms/disease-associated-microglia) — AD-specific microglial state
• [APOE gene](/genes/apoe) — Major AD genetic risk factor with neuroinflammatory effects

Eligibility and Contact

Study Sites:

• Columbia University Medical Center
• New York, NY 10032
• Principal Investigator: [To be determined]
• Contact: [NCT04840979 contact information]

Recruitment Status: RECRUITING (as of last update)

For More Information: [ClinicalTrials.gov NCT04840979](https://clinicaltrials.gov/study/NCT04840979)

References

[Wimberley et al., ^11C-ER176: Improved TSPO PET ligand with reduced polymorphism sensitivity (2017)](https://pubmed.ncbi.nlm.nih.gov/29056073/)

[Lyoo et al., ^11C-ER176 PET in Alzheimer disease: Microglial activation and genetic associations (2020)](https://pubmed.ncbi.nlm.nih.gov/32251522/)

[TSPO GWAS identifies novel variants affecting microglial activation (2019)](https://pubmed.ncbi.nlm.nih.gov/31152189/)

[Chromosome 1 variant rs2997325 affects TSPO binding (2020)](https://pubmed.ncbi.nlm.nih.gov/32038892/)

[Microglial genetic architecture in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/34054676/)

See Also

• [TSPO PET imaging mechanism](/mechanisms/tspo-pet-imaging-neuroinflammation)
• [Neuroinflammation mechanism](/mechanisms/neuroinflammation)
• [Clinical trials in Alzheimer's](/diseases/alzheimers-disease#clinical-trials)
• [PET imaging diagnostics](/diagnostics/pet-imaging)
• [Genetic biomarkers](/biomarkers/genetic-biomarkers)
• [Columbia University](/institutions/columbia-university)

Pathway Diagram

The following diagram shows the key molecular relationships involving NCT04840979 - Genetic Variants Affecting Microglial Activation in AD discovered through SciDEX knowledge graph analysis: