DECISION Study - Summary Title: Decision-making, Ethical Consent, and Interactive Dialogue in Ongoing Neurocognitive Decline

The DECISION study aims to develop and validate a simplified yet robust tool for assessing the capacity to give informed consent in patients with Alzheimer's disease and related dementias. Existing tools like the MacCAT-T are too complex for routine use, so this project focuses on creating a user-friendly, valid alternative that addresses language, attention, insight, judgment, and decision-making.

The study uses a multi-phase approach including:

• Development and validation of a new consent capacity test battery
• Correlation of cognitive decline with brain changes and biomarkers (MRI, OCT, plasma markers)
• Ethical, legal, and co-design perspectives to ensure practical and responsible application

The target group includes 100-150 participants from earlier dementia studies. The ultimate goal is to establish a clinically usable, legally sound instrument for assessing consent capacity in individuals with cognitive impairments.

Title: DECISION Study: Ethical Consent and Cognitive Decline Assessment in Dementia Detailed Study Description (Design-Focused)

1. Background and Rationale The ability to provide informed consent is central to ethical research participation and clinical decision-making. However, in individuals with neurocognitive disorders, such as Alzheimer's disease (AD), frontotemporal dementia (FTD), or vascular dementia, this capacity is often compromised. The fluctuating nature of cognitive symptoms, especially in early and mixed dementia presentations, complicates standardized assessments. Currently used instruments, such as the MacArthur Competence Assessment Tool for Treatment (MacCAT-T), are comprehensive but not suited for rapid clinical decision-making or large-scale implementation.

   Emerging therapeutic interventions and increased demand for early diagnosis necessitate scalable, valid instruments to assess capacity. DECISION seeks to close this gap by developing a tool grounded in neuropsychological theory, clinical practicality, and ethical and legal acceptability.

2. Objectives

   Primary Objective:

   • Develop a standardized, brief, and reusable tool to assess capacity to consent in individuals with neurocognitive disorders.

   Secondary Objectives:

   • Validate the tool against established standards (e.g., MacCAT-T).
   • Examine the relationship between cognitive domains (e.g., language, attention) and decision-making.
   • Investigate correlations between neurodegenerative and vascular biomarkers and consent capacity.

3. Study Design The DECISION study is structured as a two-phase, prospective cohort study with mixed-methods integration.

   Phase 1: Tool Development and Validation

   • Sample: 100-150 participants (patients with varying dementia subtypes and healthy controls).

   • Methodology:

     • Comprehensive neuropsychological profiling
     • Test item development from domains critical to decision-making (attention, executive function, language comprehension, risk assessment)
     • Use of MacCAT-T and Clinical Dementia Rating (CDR) for validation
     • Comparison of subjective and informant-reported measures (e.g., Cognitive Failures Questionnaire, Dysexecutive Questionnaire)

   • Output: A modular test battery with a shortened, clinically usable version Phase 2: Neurobiological Correlates

   • Objective: Identify biomarkers associated with impaired consent capacity

   • Biomarkers:

     • Blood-based (e.g., pTau217, NfL, GFAP, Aβ1-42/1-40)
     • Structural MRI (temporal, frontal, and parietal regions)
     • Optical coherence tomography (OCT) for retinal changes

   • Analysis: Correlation with DECISION test battery performance and clinical indicators

4. Recruitment Strategy Participants will be selected from previous cohorts (AmyClear and ActiGlia), allowing access to existing CSF, PET, and neuropsychological data. All participants will be re-consented and evaluated using standardized tools at baseline. If capacity is limited, a legal guardian or proxy will be engaged per ethical protocols.

5. Inclusion/Exclusion Criteria

   • Adults aged 50+
   • Diagnosed or suspected cognitive impairment (per ICD-10 criteria)
   • Able to provide consent or have a legal representative
   • No severe sensory impairments interfering with testing

6. Ethical Framework The study follows the Declaration of Helsinki and German civil law (BGB). All assessments are designed to be minimally invasive, with an emphasis on autonomy, transparency, and participant safety. Focus groups with medical professionals and interviews with patients will inform test development.

7. Co-Design and Participatory Approach Patients and caregivers contribute to item design and language accessibility. Medical professionals help ensure clinical relevance. Legal advisors assess conformity with consent standards.

8. Outcomes and Statistical Analysis

   • Primary endpoint: Validity and reliability of the new tool compared to MacCAT-T
   • Secondary endpoints: Biomarker correlations, subgroup analyses (e.g., dementia type, anosognosia presence)
   • Analytical methods: Correlation, regression, factor analysis, ROC curves, AUC calculations

9. Data Handling and Security Data will be pseudonymized and stored within the MeDICLMU infrastructure. Personal identifiers are kept separate and encrypted. Access is limited to the study team. Data usage will comply with GDPR.

10. Timeline

    • Study start: September 2025
    • End of recruitment: March 2026
    • Final assessments and analysis: March 2027

11. Dissemination Results will be published in peer-reviewed journals and presented at international conferences. A clinical guideline for using the consent assessment tool will be developed.

Conclusion The DECISION study aims to create a scalable, evidence-based tool for assessing capacity to consent in cognitively impaired individuals. Its integration of neuropsychology, clinical practice, ethics, and biology positions it as a model for future dementia care and research protocols.

Inclusion Criteria:

• Age ≥ 50 years
• Diagnosis or suspected diagnosis of a neurocognitive disorder (e.g., Alzheimer's disease, frontotemporal dementia, vascular dementia, mixed forms) based on ICD-10 criteria
• Ability to provide informed consent, or availability of a legally authorized representative
• Sufficient language proficiency to complete cognitive assessments
• Availability of a trusted informant (e.g., caregiver or relative) for external rating instruments
• Willingness to participate in neuropsychological testing, blood sampling, and optional imaging

Exclusion Criteria:

• Severe sensory impairments (e.g., blindness, deafness) that prevent completion of assessments
• Acute psychiatric conditions (e.g., psychosis, severe depression) that interfere with study procedures
• History of major neurological disorders unrelated to dementia (e.g., traumatic brain injury, stroke with severe residual deficits)
• Uncontrolled systemic illness or unstable medical condition
• Refusal or inability to undergo necessary procedures (e.g., blood draw, optic coherence tomography, MRI)
• Participation in another interventional study that could interfere with the outcomes of this study

The DECISION study will recruit a well-characterized cohort of 100-150 adult participants, including individuals with neurocognitive disorders as well as cognitively healthy controls. The primary focus is on individuals aged 50 years and older with suspected or confirmed diagnoses of Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular dementia, or mixed neurodegenerative pathologies. Participants may present with early-stage cognitive decline, including mild cognitive impairment (MCI), or more advanced stages of dementia.

Participants will primarily be recruited from existing clinical studies conducted at LMU University Hospital, including the AmyClear and ActiGlia cohorts. These individuals have previously undergone extensive diagnostic workups, including cerebrospinal fluid (CSF) biomarker and PET analyses.

Individual participant data (IPD) will not be shared due to the sensitivity of health-related and cognitive data in a vulnerable population. The dataset includes pseudonymized but potentially re-identifiable information, and broad data sharing would exceed the scope of participants' informed consent. Sharing is restricted to protect privacy and comply with data protection regulations (e.g., GDPR). Access may be granted upon reasonable request and ethics approval under controlled conditions.