Genetic Variants and Microglial Activation Imaging for Alzheimer's Disease

Overseen By Elena Golub

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: William Charles Kreisl

Must not be taking: Anticoagulants, Immunosuppressives, Steroids

Disqualifiers: Brain disorders, Epilepsy, Obesity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

250 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how certain genetic factors affect brain cells, known as microglia, in people with Alzheimer's disease. It uses brain imaging to observe how these cells activate and to explore their connection with gene changes. Participants will undergo PET scans with specific tracers, including 11C-ER176 and 18F-florbetaben, to visualize these processes. The trial seeks individuals with Alzheimer's or mild cognitive impairment, as well as healthy volunteers, who are fluent in English and can participate in various tests over five years. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial excludes participants who are taking anticoagulant or immunosuppressive medications, and those who have used steroids in the 30 days before the PET scan. If you are on these medications, you may need to stop taking them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that 11C-ER176 remains under study, and limited information exists on its safety for Alzheimer's patients. However, it produces clear images, which aids research. Currently, clear safety data for Alzheimer's patients is unavailable.

In contrast, 18F-florbetaben has seen more frequent use. Tested in 872 adults, it is considered safe for imaging in Alzheimer's disease and other memory issues. It helps doctors visualize amyloid plaques in the brain, which are linked to Alzheimer's. The safety of florbetaben is well-documented, making it a more established choice.

In summary, 18F-florbetaben has a proven record of safe use in humans, while 11C-ER176 continues to be researched. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these imaging agents, 11C-ER176 and 18F-florbetaben, because they offer new ways to visualize and understand Alzheimer's disease. Unlike traditional treatments that aim to slow symptoms, these compounds allow for detailed brain imaging to see microglial activation and amyloid plaques, key features of Alzheimer's. This imaging could lead to earlier and more accurate diagnoses, helping to tailor treatments more effectively and monitor their impact over time.

What evidence suggests that this trial's treatments could be effective for Alzheimer's disease?

In this trial, participants with cognitive impairment will undergo a PET scan with 11C-ER176. Research shows that this tracer identifies active microglia in the brain, which play a role in Alzheimer's disease. Microglia are brain cells that fight infections and clean up waste. Studies have found that 11C-ER176 binds well to these active microglia, making them easier to see on PET scans.

Participants may also undergo an 18F-florbetaben PET scan if they lack known AD biomarkers. Research indicates that 18F-florbetaben detects amyloid plaques in the brain, which are linked to Alzheimer's. In studies, most people with Alzheimer's and some with mild memory problems showed significant plaque presence with this scan. This aids in early diagnosis and understanding disease progression. Both tools aim to enhance understanding of Alzheimer's and its impact on the brain. ^{6 7 8 9 10}

Who Is on the Research Team?

Philip De Jager, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for white, non-Hispanic or Latino individuals aged 50+, fluent in English, with mild Alzheimer's or no cognitive impairment. Participants must have a certain Clinical Dementia Rating and be able to consent. They need prior AD biomarker results or will undergo a PET scan. Exclusions include severe medical conditions, MRI contraindications, recent excessive research radiation exposure, chronic inflammatory/infectious diseases, and other brain disorders.

Inclusion Criteria

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

Subjects must be able to provide informed consent

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

Exclusion Criteria

I have a history of brain disorders other than mild cognitive impairment or Alzheimer's.

You have participated in a clinical trial for a drug that changes the course of Alzheimer's disease in the past year.

I have a chronic inflammatory or infectious disease like MS, IBD, RA, psoriasis, lupus, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

PET Imaging and Genetic Analysis

Participants undergo PET imaging with 11C-ER176 and genome-wide genetic analysis

1-2 weeks

1 visit (in-person)

Annual Clinical Evaluation

Participants undergo annual clinical evaluation and blood sample collection to establish the trajectory of AD-related serum biomarkers and syndromic diagnoses

5 years

5 visits (in-person, annually)

Follow-up

Participants are monitored for safety and effectiveness after the main study activities

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 11C-ER176
• 18F-florbetaben

Trial Overview The study tests how gene variants affect microglial activation in Alzheimer's using PET imaging agents: 11C-ER176 and 18F-florbetaben. It aims to validate known genetic influences on activated microglia proportion and discover new gene loci related to this process while assessing the functional impact of these variants.

How Is the Trial Designed?

Group I: Cognitive Impairment Experimental Treatment 2 Interventions

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 II: No Cognitive Impairment Active Control 2 Interventions

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.

Who Is Running the Clinical Trial?

William Charles Kreisl

Lead Sponsor

Trials

7

Recruited

520+

Edward D Huey, MD

Lead Sponsor

Trials

1

Recruited

250+

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

In a study of 24 participants with varying stages of Alzheimer's disease, increased microglial activation was observed in the hippocampus of those classified as progressors or symptomatic, indicating a potential link between neuroinflammation and disease progression.

Higher baseline levels of microglial activation, measured by the [11C]PK11195 PET imaging, were predictive of cognitive decline over time, suggesting that monitoring neuroinflammation could be important for understanding Alzheimer's disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease. Wang, Q., Chen, G., Schindler, SE., et al.[2023]

[(18)F]florbetaben is a highly accurate PET imaging agent that effectively detects β-amyloid plaques in the brain, demonstrating high sensitivity and specificity in identifying Alzheimer's disease and other cognitive impairments based on a phase III study.

The agent is generally well tolerated, with only mild to moderate adverse reactions reported, primarily related to the injection site, and no serious adverse events associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(18)F]Florbetaben: a review in β-amyloid PET imaging in cognitive impairment. Syed, YY., Deeks, E.[2022]

In the ongoing phase 1b PRIME study involving patients with prodromal or mild Alzheimer's disease, aducanumab treatment led to significant reductions in amyloid PET SUVR, indicating a decrease in amyloid plaque burden over time and with higher doses.

The choice of reference regions for calculating SUVR significantly influenced effect sizes, with subcortical white matter and the pons yielding the largest effect sizes, while using the anterior cingulate cortex as a target ROI provided better results than a composite cortex approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab. Chiao, P., Bedell, BJ., Avants, B., et al.[2019]

In a study of 93 Alzheimer's disease patients, significant associations were found between certain genetic variants (APOEɛ4 and PTK2B rs28834970) and the presence of cerebral amyloid angiopathy (CAA), a common pathology in Alzheimer's.

The research also indicated that variants in PTK2B, PICALM, and CR1 may influence microglial activation in white matter, suggesting these genetic factors could modify disease progression through their effects on amyloid-β metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Associations of Alzheimer's Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures. Sakae, N., Heckman, MG., Vargas, ER., et al.[2021]

In a study involving two individuals with sporadic Alzheimer's disease (AD) and 107 control subjects, F-FDG PET imaging revealed that brain glucose metabolism declined significantly faster in the AD subjects (approximately 9% over 9-12 years) compared to the control group (2.2% per decade due to aging).

The decline in F-FDG uptake began 4 years and 2 years before memory loss was observed in the two AD subjects, suggesting that cognitive decline may occur sooner in sporadic AD than previously thought in dominantly inherited forms of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal 18F-FDG Images in Patients With Alzheimer Disease Over More Than 9 Years From a Preclinical Stage. Ishibashi, K., Onishi, A., Wagatsuma, K., et al.[2021]

In an Alzheimer's disease (AD) animal model, increased glucose uptake in the hippocampus was linked to altered microglial metabolism, suggesting that microglia play a significant role in the disease's progression.

Human brain imaging data indicated that higher hippocampal glucose uptake, measured by FDG PET, correlates with soluble TREM2 levels and can predict the conversion from mild cognitive impairment to Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hippocampal glucose uptake as a surrogate of metabolic change of microglia in Alzheimer's disease. Choi, H., Choi, Y., Lee, EJ., et al.[2022]

Florbetapir (18F) is a promising PET tracer that effectively binds to amyloid-β plaques, allowing for the differentiation of Alzheimer's disease patients from healthy individuals, as demonstrated in phase I and II clinical trials with clear imaging results.

The tracer shows fast kinetics, with optimal imaging quality achieved within 5 to 10 minutes post-injection, and has a strong correlation with postmortem assessments of amyloid deposition, indicating its potential for early detection of Alzheimer's disease without serious adverse events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Florbetapir (18F), a PET imaging agent that binds to amyloid plaques for the potential detection of Alzheimer's disease. Okamura, N., Yanai, K.[2016]

Florbetapir PET imaging effectively distinguishes between amyloid levels in individuals with probable Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHCs), with significant differences in amyloid burden observed among these groups.

The study established specific thresholds for florbetapir SUVRs that indicate pathological amyloid levels associated with AD, providing a reliable method for assessing amyloid presence in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Fleisher, AS., Chen, K., Liu, X., et al.[2022]

The use of 18 F-PBR06 PET imaging revealed increased glial activation in specific brain regions of a 69-year-old woman diagnosed with Alzheimer's disease, indicating a potential biomarker for disease progression.

Over a 6-year follow-up, the patient's cognitive impairment worsened from mild to moderate, highlighting the progressive nature of Alzheimer's disease and the importance of monitoring brain changes over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Microglial Activation in Alzheimer Disease Using 18 F-PBR06 PET. Carter, K., Cicero, S., Rissanen, E., et al.[2023]

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Neuroinflammation Biomarkers in the AT(N) Framework ... The [11C]ER176 presents favorable kinetics (118), high signal-to-noise ratio, and volume of distribution stability (119), however, no data with AD patients is ...