Diagnostic Test for Alzheimer's Disease

(DTAD Trial)

Recruiting at2 trial locations

Overseen by Wendy Qiu, MD PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Waitlist Available

Sponsor: Boston University

Must not be taking: Insulin, Pramlintide, GLP-1, others

Disqualifiers: Diabetes, Stroke, Seizures, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

In this multi-center study, the investigators plan to develop a simple blood-based test for early detection of Alzheimer's disease (AD). The test is based on a single injection of Pramlintide, an amylin analogue and FDA-approved drug currently used for treatment of diabetes. The investigative team has provided evidence in humans with full-blown AD and AD-relevant mouse models that a single injection of Pramlintide transiently renders the blood brain barrier (BBB) more permeable to Amyloidbeta (Aß) peptides, allowing their efflux from the brain compartment into the blood. This Aß efflux causes a corresponding transient elevation of blood levels of Aß, the magnitude of which the applicants believe is proportional to the brain amyloid load as determined by AV-45 PET. The measured difference in the level of plasma Aß taken just before and a short time after injection should reveal the magnitude of the transient increase in blood Aß levels. Supportive preliminary data comes from later stage (full-blown) AD patients with more in-depth background studies in Tg2576 and 5X Familial Alzheimer's Disease (FAD) mouse models. If successful for use as an early AD (i.e., at the Mild Cognitive Impairment \[MCI\] stage) biomarker, this could be a game-changer for both early AD diagnostics and clinical trials aimed at identifying and testing the efficacy of drugs useful for treatment of AD at early stages. If Pramlintide is effective in releasing mobile pools of Aß from the brain into the blood, this could also have some therapeutic potential, with the goal of reducing brain amyloid load. Three groups of particpants will be studied: 1) amnestic MCI with or without positive AD imaging pathology, 2) probable AD with positive imaging AD pathology, and 3) controls who have normal cognition and do not have memory complaints.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically insulin, pramlintide, other injectable anti-diabetic drugs, and oral anti-diabetic products. If you are on any of these, you would need to discontinue them to participate.

How is this Alzheimer's disease diagnostic test different from other treatments?

This diagnostic test for Alzheimer's disease is unique because it focuses on detecting specific biomarkers, like misfolded Aβ oligomers, in cerebrospinal fluid, which allows for early and sensitive diagnosis. Unlike traditional methods that rely on neuropsychological tests or post-mortem analysis, this test offers a non-invasive and objective way to identify Alzheimer's disease with high sensitivity and specificity. ^{1 2 3 4 5}

Research Team

Wendy Qiu, MD PhD

Principal Investigator

Boston Medical Center and BUSM

Eligibility Criteria

This trial is for individuals with mild cognitive impairment or Alzheimer's, who are part of certain research centers and have a BMI between 20-35. Participants must not have diabetes, recent infections, history of stroke or brain injury, seizures, or use related medications. Those with probable AD need confirmed pathology and a designated proxy.

Inclusion Criteria

Probable AD subjects must be confirmed for positive AD pathology in the CNS

Probable AD subjects must have a designated research proxy signed before they became demented.

Current research subjects at the BU ADC, VA BHS, or IU ADC

Exclusion Criteria

Unexplained hypoglycemia (glucose ≤ 60 mg/dL) or hyperglycemia (glucose ≥ 126 mg/dL) pre-injection

I have had a brain injury with loss of consciousness.

I have diabetes.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pramlintide Challenge Test

Participants receive a single injection of Pramlintide to assess blood-brain barrier permeability and measure plasma Aβ levels

1 day

1 visit (in-person)

Immediate Monitoring

Plasma Aβ and t-tau changes, as well as plasma inflammatory and metabolic changes, are measured at multiple time points after the challenge test

180 minutes

1 visit (in-person)

Follow-up

Participants are monitored for changes in cognitive and biomarker outcomes at 12 and 24 months post challenge

24 months

2 visits (in-person)

Treatment Details

Interventions

• Pramlintide (Amylin Analogue)

Trial Overview Researchers are testing a blood-based diagnostic test for early Alzheimer's detection using Pramlintide. This drug may allow Amyloidbeta peptides to move from the brain into the blood after injection, potentially indicating brain amyloid levels.

Participant Groups

Group I: Probable AD Experimental Treatment 1 Intervention

Participants with probable AD with positive imaging AD pathology will receive the pramlintide challenge test.

Group II: Amnestic MCI Active Control 1 Intervention

Participants with amnestic MCI with or without positive AD imaging pathology will receive the pramlintide challenge test.

Group III: Control- Normal Cognition Active Control 1 Intervention

Participants with normal cognition without any memory complaints will receive the pramlintide challenge test.

Who Is Running the Clinical Trial?

Boston University

Lead Sponsor

Trials

494

Recruited

9,998,000+

Sophie Kornowski

Boston University

Chief Executive Officer since 2022

MBA from the University of Chicago, Doctorate in Pharmacy from Paris Descartes University

Dr. Patrizia Cavazzoni

Boston University

Chief Medical Officer

MD from McGill University

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Dr. Richard J. Hodes

National Institute on Aging (NIA)

Chief Executive Officer since 1993

MD from Harvard Medical School

Dr. Marie Bernard

National Institute on Aging (NIA)

Chief Medical Officer

MD from Harvard Medical School

Findings from Research

The ideal biomarker for Alzheimer's disease should have over 80% sensitivity and specificity, be non-invasive, and validated through multiple independent studies, ensuring reliability and reproducibility.

For early-onset familial Alzheimer's, mutations in specific genes (presenilin 1, presenilin 2, and amyloid precursor protein) are key indicators, while in late-onset cases, the presence of the apolipoprotein E e4 allele and cerebrospinal fluid levels of Abeta42 and tau are more relevant for diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. [2022]

In a study involving 771 participants over 18 months, a decrease in the ratio of plasma Aβ1-42 to Aβ1-40 was found in patients with Alzheimer's disease, indicating a potential biomarker for early diagnosis.

Plasma Aβ1-42 levels also decreased in individuals with mild cognitive impairment and those transitioning from healthy to mild cognitive impairment, suggesting that monitoring these levels could help track disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer's disease. Rembach, A., Faux, NG., Watt, AD., et al.[2022]

Current diagnostic tests for Alzheimer's disease (AD) are improving early diagnosis, but definitive diagnosis still relies on autopsy findings of amyloid plaques and neurofibrillary tangles.

Research is focusing on developing less invasive peripheral biomarkers from skin or blood samples, which may offer high sensitivity and specificity for diagnosing AD and tracking its progression, addressing limitations of cerebrospinal fluid (CSF) biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral biomarkers of Alzheimer's disease. Khan, TK., Alkon, DL.[2015]

A new biochemical test called Aβ-PMCA can detect misfolded Aβ oligomers in cerebrospinal fluid, which are crucial in the development of Alzheimer's disease, with a sensitivity of 90% and specificity of 92%.

This method can differentiate Alzheimer's patients from those with other neurodegenerative or neurological disorders, providing a promising approach for early and accurate diagnosis of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of misfolded Aβ oligomers for sensitive biochemical diagnosis of Alzheimer's disease. Salvadores, N., Shahnawaz, M., Scarpini, E., et al.[2022]

Identifying biomarkers for Alzheimer's disease (AD) could lead to more accurate and less invasive diagnoses, moving beyond the traditional reliance on autopsy evaluations.

Promising fluid and imaging biomarkers have been discovered that may help detect preclinical AD, allowing for earlier intervention and better predictions of disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers of Alzheimer's disease. Craig-Schapiro, R., Fagan, AM., Holtzman, DM.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer's disease. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Peripheral biomarkers of Alzheimer's disease. [2015]

4. United States pubmed.ncbi.nlm.nih.gov

Detection of misfolded Aβ oligomers for sensitive biochemical diagnosis of Alzheimer's disease. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Biomarkers of Alzheimer's disease. [2021]