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

NCT ID: NCT04840979

Last Updated: 2025-04-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-11
• Study Completion Date: 2026-12-31

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.

Detailed Description

While activated microglia have been observed in the vicinity of neuritic amyloid plaques in Alzheimer's disease (AD), there have been no large-scale assessments of microglial activation in aging and neurodegenerative disease. The investigators seek to understand the genetic underpinning of microglial responses-particularly the proportion of microglia in a morphologically-defined state of activation-that increase susceptibility to AD, so the investigators can develop more targeted forms of immune-based therapies to prevent cognitive decline and progression to dementia. The objective is to refine the genetic architecture of microglial activation to validate a previously identified gene variant -- and to identify novel loci -- that influence the proportion of activated microglia. The investigators also seek to understand the functional consequences of variants driving microglial activation in AD.

The central hypothesis is that identifiable gene variants influence microglial activation and susceptibility to AD. The investigators will test this hypothesis by conducting genome-wide analysis and identifying associations between gene variants and microglial activation. Microglial activation will be measured in human autopsy tissue (ex vivo), living human brain using PET imaging (in vivo), and in monocyte-derived microglia-like cells (in situ and in vitro).

This genetic study is designed to validate a finding that was discovered in participants with self-reported European-Caucasian ancestry. Therefore, the study seeks to enroll participants who self-report as white, not Hispanic or Latino. However, if this study is successful, the investigators plan to use the methods in this protocol in a future study to identify new genetic variants associated with changes on TSPO PET in a more diverse participant population. The investigators intend to use the results from this study to eventually benefit individuals of all racial and ethnic groups.

Conditions

Alzheimer Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Cognitive Impairment

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.

Group Type: EXPERIMENTAL

11C-ER176

Intervention Type: 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.

18F-florbetaben

Intervention Type: DRUG

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

No Cognitive Impairment

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.

Group Type: ACTIVE_COMPARATOR

11C-ER176

Intervention Type: 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.

18F-florbetaben

Intervention Type: DRUG

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

Interventions

11C-ER176

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.

Intervention Type: DRUG

18F-florbetaben

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

Intervention Type: DRUG

Other Intervention Names

[11C]ER176; [18F] Florbetaben

Eligibility Criteria

Inclusion Criteria

1. Age 50 and older at time of study entry.

2. 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.

3. 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.

4. 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.

5. Self-identify as white, non-Hispanic or Latino

6. Subjects must be ableto provide informed consent

7. Written and oral fluency in English

8. Able to participate in all scheduled evaluations and to complete all required tests and procedures.

9. 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.

Exclusion Criteria

1. Past or present history of certain brain disorders other than MCI or AD.

2. Certain significant medical conditions, which make study procedures of the current study unsafe. Such serious medical conditions include uncontrolled epilepsy and multiple serious injuries.

3. Contraindication to MRI scanning

4. Conditions precluding entry into the scanners (e.g. morbid obesity, claustrophobia, etc.).

5. Exposure to research related radiation in the past year that, when combined with this study, would place subjects above the allowable limits.

6. Participation in the last year in a clinical trial for a disease modifying drug for AD.

7. Inability to have a catheter in subject's vein for the injection of radioligand.

8. Inability to have blood drawn from subject's veins.

9. Taking anticoagulant (e.g., warfarin) or immunosuppressive/immunomodulatory medication. Nonsteroidal anti-inflammatory drugs (NSAIDs) are not exclusionary. Use of steroids in the 30 days preceding the PET scan.

10. 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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Philip De Jager

Weil-Granat Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Philip De Jager, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Irving Medical Center

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Galen Ziaggi

Role: CONTACT

gfz2102@cumc.columbia.edu

212-305-9079

Elena Golub

Role: CONTACT

eg2972@cumc.columbia.edu

212-305-9079

Facility Contacts

Galen Ziaggi

Role: primary

gfz2102@cumc.columbia.edu

212-305-9079

Other Identifiers

RF1AG070438

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AAAT2774

Identifier Type: -

Identifier Source: org_study_id