Discovery and Validation of Genetic Variants Affecting Microglial Activation in Alzheimer's Disease

NCT04840979 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: AAAT2774RF1AG070438
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objectives are to validate that a previously identified gene variant influences the proportion of activated microglia (PAM) and the amount of TSPO binding on PET imaging, to identify novel loci that influence PAM and TSPO PET, and to understand the functional consequences of gene variants that drive microglial activation in Alzheimer's disease.

Conditions

Alzheimer Disease

Keywords

PET scan; Inflammation; Genetic testing; Cognitive Impairment

Outcome Measures

Primary Outcomes (2)

• Correlation between the chromosome 1 variant (rs2997325) and TSPO binding

  The measure will be in vivo validation of GWAS and assessment of clinical relevance by performing TSPO PET imaging using 11C-ER176 to measure microglial activation. PET images will be analyzed using 1) the two-tissue kinetic model to calculate total distribution volume, corrected for free fraction of radioligand in plasma (VT/fP). Analysis will be a meta-analysis of the association of rs2997325 with 11C-ER176 binding (total distribution volume, VT).

  Up to 1 year

• Number of variants discovered in genome-wide association study (GWAS) that influence TSPO binding

  11C-ER176 data will be used to perform a discovery GWAS for additional variants that influence TSPO binding and to define the genetic architecture of the PAM trait. Using PLINK and all imputed high quality genotypes (imputation r2 \>0.8), adjusted for sex, age, and technical variables, the investigators will perform a GWAS for TSPO binding.

  Up to 1 year

Study Arms (2)

Cognitive Impairment

EXPERIMENTAL

Subjects diagnosed with Alzheimer's disease (AD) or mild cognitive impairment (MCI) will have one PET scan with 11C-ER176, with arterial sampling. If the subject lacks known AD-biomarkers, they may undergo a 18F-florbetaben PET scan prior to the 11C-ER176 PET scan. Genome-wide genetic analysis will be performed. Participants will undergo an annual clinical evaluation and blood sample collection for 5 years to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses.

Drug: 11C-ER176; Drug: 18F-florbetaben

No Cognitive Impairment

ACTIVE COMPARATOR

Healthy volunteers who are cognitively normal will have one PET scan with 11C-ER176, with arterial sampling. If the subject lacks known AD-biomarkers, they may undergo an 18F-florbetaben PET scan prior to the 11C-ER176 PET scan. Genome-wide genetic analysis will be performed. Participants will undergo an annual clinical evaluation and blood sample collection for 5 years to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses.

Drug: 11C-ER176; Drug: 18F-florbetaben

Interventions

11C-ER176 DRUG

11C-ER176 is a novel TSPO radioligand that was developed because of its relative insensitivity to the rs6971 polymorphism. Increased TSPO signal on PET is associated with activation of microglia in the brain. The radioligand will be administered in tracer doses at activity of up to 20 mCi (740 MBq), IV, total of one injection. A single dose of radioligand will be injected over 1 minute.

Also known as: [11C]ER176

Cognitive Impairment; No Cognitive Impairment

18F-florbetaben DRUG

Florbetaben has been approved by the FDA to help diagnose Alzheimer's disease. Florbetaben measures amyloid in the brain.

Also known as: [18F] Florbetaben

Cognitive Impairment; No Cognitive Impairment

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 50 and older at time of study entry.
• Meet criteria for either a) amnestic mild cognitive impairment (single or mixed domain) or Alzheimer's disease, or b) have no cognitive impairment, based on history, exam, and neuropsychological testing.
• Patients must have Clinical Dementia Rating Scale score of 0.5 or 1 at enrollment. Controls must have Clinical Dementia Rating scale score of 0 at enrollment.
• Subjects must have AD biomarker previously obtained for research or clinical purposes or undergo a 18F-florbetaben PET scan during the screening process. Patients must have positive amyloid PET scan or CSF results consistent with AD. Controls must have a negative amyloid PET scan or CSF results not consistent with AD.
• Self-identify as white, non-Hispanic or Latino
• Subjects must be ableto provide informed consent
• Written and oral fluency in English
• Able to participate in all scheduled evaluations and to complete all required tests and procedures.
• In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study.

You may not qualify if:

• Past or present history of certain brain disorders other than MCI or AD.
• Certain significant medical conditions, which make study procedures of the current study unsafe. Such serious medical conditions include uncontrolled epilepsy and multiple serious injuries.
• Contraindication to MRI scanning
• Conditions precluding entry into the scanners (e.g. morbid obesity, claustrophobia, etc.).
• Exposure to research related radiation in the past year that, when combined with this study, would place subjects above the allowable limits.
• Participation in the last year in a clinical trial for a disease modifying drug for AD.
• Inability to have a catheter in subject's vein for the injection of radioligand.
• Inability to have blood drawn from subject's veins.
• Having a diagnosis of a chronic inflammatory disease (for example, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus) or a chronic infectious disease such as H.I.V.

Sponsors & Collaborators

• Columbia University: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

MeSH Terms

Conditions

Alzheimer Disease; Inflammation; Cognitive Dysfunction

Interventions

4-(N-methylamino)-4'-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)stilbene

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cognition Disorders

Study Officials

• Philip De Jager, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Galen Ziaggi

CONTACT

212-305-9079; gfz2102@cumc.columbia.edu

Elena Golub

CONTACT

212-305-9079; eg2972@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Weil-Granat Professor of Neurology

Study Record Dates

• First Submitted: April 8, 2021
• First Posted: April 12, 2021
• Study Start: May 11, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 24, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: Up to two weeks after review and approval of request.
• Access Criteria: Investigator qualifications and previous work will be reviewed by PI. Subsequent email correspondence will relay technical criteria needed for access.

Locations

US (1)