Risk Disclosure for Mild Cognitive Impairment

Overseen By Corey J Bolton, PsyD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Vanderbilt University Medical Center

Disqualifiers: Schizophrenia, Bipolar, Epilepsy, others

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

Compensation: Varies

Number of Visits: 3

44 Participants Needed

Trial Summary

What is the purpose of this trial?

Novel blood-based biomarkers of Alzheimer's disease (AD), such as plasma levels of tau phosphorylated at threonine 181 (p-tau181), have shown great promise in detecting early AD pathology. While current studies point to this biomarker as having great clinical utility, one necessary step before clinical implementation is developing safe and effective methods for disclosure of results. Past risk disclosure studies have shown that disclosing risk for AD based on genetics or amyloid status is safe, but these studies have largely focused on cognitively unimpaired individuals. This study seeks to develop comprehensible educational materials to aid risk disclosure and examine the effect of risk disclosure based on plasma p-tau181 results in a group of participants with mild cognitive impairment (MCI) at imminent risk of converting to dementia. First, educational materials will be developed in collaboration with health communication experts and then refined in focus groups made up of individuals with MCI. Educational materials will be analyzed on several key reading and comprehensibility metrics and will include personalized risk estimate based on a well-accepted risk algorithm (Cullen, et al., 2021). Next, these educational materials will be utilized to disclose risk in a randomized controlled trial with an active control arm receiving disclosure based on age, sex, and cognitive status (based on Mini-Mental State Examination), meant to mimic common methods of clinical diagnostic and prognostic decision making, and an intervention arm receiving disclosure based on the above factors plus plasma p-tau181 results. Outcomes will include measures of comprehension and psychological well-being (anxiety, depression, hopelessness, and distress) and will be assessed immediately after risk disclosure and again at six-month follow-up. It is hypothesized that risk disclosure based on plasma p-tau181 is not more psychologically harmful or less comprehensible than disclosure based on demographic factors and MMSE. This pilot study will provide a necessary step towards moving plasma p-tau biomarkers towards safe clinical implementation and will develop educational materials that can be utilized in future studies and clinical practice.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

Is plasma p-tau181 safe for humans?

The research articles focus on the use of plasma p-tau181 as a biomarker for Alzheimer's disease, but they do not provide specific safety data for its use in humans. ^{1 2 3 4 5}

How does this treatment for mild cognitive impairment differ from other treatments?

The treatment focuses on using plasma phosphorylated tau (p-tau) levels as a biomarker to track and predict cognitive decline, which is a novel approach compared to traditional treatments that may not use such specific biomarkers for monitoring disease progression. ^{1 4 5 6 7}

Research Team

Corey J Bolton, PsyD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for adults aged 60 and older with a diagnosis of amnestic mild cognitive impairment (MCI) from the Vanderbilt Alzheimer's Disease Research Center. They must have someone who interacts with them regularly to participate in study visits, speak English fluently, and be able to consent. Those with major psychiatric or neurological illnesses, significant head injuries, or acute psychological distress are excluded.

Inclusion Criteria

Consensus diagnosis of amnestic MCI by Vanderbilt Alzheimer's Disease Research Center (VADRC) clinician panel

English language fluency

I am 60 years old or older.

Exclusion Criteria

I am able to understand and make decisions about participating in this study.

History of major psychiatric illness (e.g., schizophrenia, bipolar), neurological illness (e.g., epilepsy, multiple sclerosis, Parkinson's disease), or head injury with significant loss of consciousness

Presence of acute psychological distress (i.e., Geriatric Depression Scale >10 at screening)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Educational Material Development

Development and refinement of educational materials in collaboration with health communication experts and focus groups

4-6 weeks

Risk Disclosure

Participants receive risk disclosure based on plasma p-tau181 results and other demographic factors

1 week

1 visit (in-person)

Follow-up

Participants are monitored for comprehension and psychological well-being after risk disclosure

6 months

2 visits (in-person)

Treatment Details

Interventions

• Plasma p-tau risk disclosure
• Standard risk disclosure

Trial Overview The study tests how best to inform people about their risk of developing dementia using a new blood test that measures plasma p-tau181 levels compared to standard methods based on age, sex, and cognitive status. Participants will receive educational materials developed by experts and their understanding and emotional well-being will be tracked immediately after disclosure and at six months.

Participant Groups

Group I: Plasma p-tau Disclosure Experimental Treatment 1 Intervention

To receive risk estimate based on plasma p-tau results in addition to age, sex, and cognitive screening score.

Group II: Standard Disclosure Active Control 1 Intervention

To receive risk estimate based on age, sex, and cognitive screening score.

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Findings from Research

In a study of 1184 participants, including cognitively normal individuals and those with mild cognitive impairment or Alzheimer's dementia, plasma phosphorylated tau181 (p-tau181) levels were found to be significantly higher in those with cognitive impairment and Alzheimer's, indicating its potential as a biomarker for disease progression.

The increase in plasma p-tau181 over time was associated with various Alzheimer's disease-related changes, such as abnormal cerebrospinal fluid biomarkers, amyloid accumulation, brain atrophy, and cognitive decline, suggesting that p-tau181 could be a useful noninvasive tool for monitoring disease progression and treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer's disease. Chen, SD., Huang, YY., Shen, XN., et al.[2021]

Blood levels of phosphorylated tau (p-tau231 and p-tau181) are significantly elevated in Alzheimer's disease (AD) patients compared to controls, indicating their potential as effective biomarkers for diagnosis, with area under the curve (AUC) values ranging from 82.2% to 90.2% across different sample types.

The study found strong correlations between serum and plasma p-tau levels, suggesting that serum could be a viable alternative for p-tau analysis in clinical settings, although absolute concentrations should be interpreted independently between serum and plasma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnostic value of serum versus plasma phospho-tau for Alzheimer's disease. Kac, PR., Gonzalez-Ortiz, F., Simrén, J., et al.[2022]

The new Simoa plasma assay for phosphorylated tau (p217+tau) shows significantly elevated levels in cognitively impaired individuals with amyloid beta (Aβ) compared to cognitively unimpaired individuals, indicating its potential as a biomarker for Alzheimer's disease.

The plasma p217+tau levels correlate strongly with amyloid and tau PET imaging results, suggesting that this assay could be a reliable tool for early detection and assessment of Alzheimer's disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum. Doré, V., Doecke, JD., Saad, ZS., et al.[2022]

Plasma levels of phosphorylated tau at threonine 181 (p-tau181) can accurately distinguish between pathology-confirmed Alzheimer's disease (AD) and normal cognition (NC) individuals, achieving a high accuracy with an AUC of 0.93.

Higher levels of p-tau181 are linked to a faster decline in cognitive function and a shorter time to significant functional decline in both mild cognitive impairment (MCI) and AD dementia patients, indicating its potential as a biomarker for disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma phosphorylated tau181 predicts cognitive and functional decline. Tropea, TF., Waligorska, T., Xie, SX., et al.[2023]

In a study of 44 individuals (24 presenilin-1 E280A carriers and 20 non-carriers), higher levels of plasma p-tau217 were found in carriers, indicating a potential link to Alzheimer's disease pathology.

Baseline plasma p-tau217 levels were predictive of future amyloid and tau PET pathology as well as cognitive performance, suggesting its utility as a non-invasive biomarker for diagnosing and monitoring Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease. Aguillon, D., Langella, S., Chen, Y., et al.[2023]

The novel plasma p-tau181 assay is highly effective in detecting both clinical Alzheimer's disease (AD) and asymptomatic amyloid-β (Aβ) pathology, with an impressive accuracy (AUC of 0.98 for clinical AD and 0.84 for asymptomatic Aβ pathology) based on a study involving 44 AD patients and 40 spouse controls.

In contrast, the p-tau231 assay did not demonstrate the same level of efficacy, indicating that p-tau181 is a superior biomarker for identifying AD-related changes in the brain, particularly in asymptomatic individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phospho-specific plasma p-tau181 assay detects clinical as well as asymptomatic Alzheimer's disease. De Meyer, S., Vanbrabant, J., Schaeverbeke, JM., et al.[2023]

In a study involving 250 participants over a median of 4.3 years, plasma levels of phosphorylated tau at threonine-217 (p-tau217) were found to increase significantly in individuals with preclinical and prodromal Alzheimer's disease, indicating its potential as a biomarker for monitoring disease progression.

Patients with mild cognitive impairment who later developed Alzheimer's dementia showed accelerated increases in p-tau217 compared to those who did not convert, suggesting that p-tau217 could help identify individuals at higher risk for progression to Alzheimer's.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease. Mattsson-Carlgren, N., Janelidze, S., Palmqvist, S., et al.[2021]

References

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

Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer's disease. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Diagnostic value of serum versus plasma phospho-tau for Alzheimer's disease. [2022]

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

Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum. [2022]

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

Plasma phosphorylated tau181 predicts cognitive and functional decline. [2023]

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

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease. [2023]

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

Phospho-specific plasma p-tau181 assay detects clinical as well as asymptomatic Alzheimer's disease. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease. [2021]