Assessing Tools That Predict and Stage Mild Cognitive Impairment
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Conversion from Cognitively Normal (CN) pTau217 Negative to pTau217-Positive
研究概览
简要总结
The goal of this observational study is to learn how well a multimodal "Progression and Risk" (PR) model can predict and stage early mild cognitive impairment (MCI) due to Alzheimer's disease in cognitively normal or very mildly impaired ApoE4-positive adults aged 55 and older. The main questions it aims to answer are:
Can a prespecified proteogenomic PR model accurately predict conversion from cognitively normal (CN) or very mildly impaired status to pTau217-positive MCI Stage I within 24 months in ApoE4-positive adults?
Does adding digital monitoring features (e.g., sleep, activity, speech), EMR-lifestyle risk scores, and plasma biomarkers to a polygenic risk score (PRS) meaningfully improve risk stratification and time-to-conversion prediction compared with simpler models (e.g., PRS alone or standard clinical risk factors)?
If there is a comparison group: Researchers will compare performance of the full multimodal PR model (integrating PRS, plasma proteomics and other omics, digital monitoring, and EMR-lifestyle data) with simpler or reduced models (for example, PRS-only, biomarker-only, or models without continuous digital monitoring) to see if the full model provides higher discrimination (AUC/ROC), better calibration, and improved time-to-conversion prediction for CN to pTau217-positive MCI transitions.
Participants will:
Provide prior genomic data (ApoE genotype and whole-genome sequencing or high-density genotyping array data) for calculation of an ancestry- and sex-normalized Alzheimer's disease PRS and assignment to PRS-based risk strata.
Attend an in-person baseline visit and follow-up visits at months 6, 12, 18, and 24 (±2 months) for clinical evaluation, neurocognitive testing (including CDR and digital cognitive batteries), and venous or capillary blood collection for plasma pTau217 and other AD biomarkers, proteomic and methylome panels, and routine safety labs when indicated.
Use digital devices (e.g., Oura Ring and smartphone-based tools) for continuous or frequent remote monitoring of sleep, activity, heart rate metrics, mobility/location, and speech-linked digital cognitive tasks, with adherence checks at study visits.
Undergo optional or sub-cohort procedures as clinically indicated or as resources allow, such as EEG, retinal hyperspectral imaging, MRI, or amyloid PET, and optionally allow clinically indicated lumbar puncture CSF samples and external clinical data to be shared with the study for exploratory biomarker analyses.
详细描述
This is an observational, first-in-human (FIH) cohort study that follows ApoE4-positive adults over two years to see how well a multimodal "Progression and Risk" (P&R) model can predict who will develop very early, biomarker-confirmed mild cognitive impairment (MCI) due to Alzheimer's disease. The study combines genetic risk, blood biomarkers, digital testing, and wearable data to stage risk in people who are currently cognitively normal or only very mildly affected.
Background and motivation Alzheimer's disease usually develops slowly over many years, beginning with a long "preclinical" phase in which people are cognitively normal but silently accumulate disease-related changes in the brain. During this period, subtle cognitive shifts may occur before symptoms reach the level of MCI or dementia. Blood and spinal fluid markers of phosphorylated tau 217 (pTau217) have emerged as highly accurate indicators of underlying Alzheimer's pathology and predictors of progression from MCI to dementia, with performance (AUC values) in the 0.8-0.9 range in prior work. The Clinical Dementia Rating scale, particularly the Sum of Boxes (CDR-SB), is a well-validated way to stage people from normal cognition through very mild impairment and MCI, where even small changes reflect meaningful clinical transitions.
However, tools like the CDR typically require an informant and are not routinely used in primary care for people who appear cognitively normal. At the same time, large genetic studies have shown that late-onset Alzheimer's is highly polygenic: many common genetic variants, along with the APOE ε4 allele, together shape an individual's inherited risk. Polygenic risk scores (PRS) summarize this inherited risk by combining information across thousands of genetic variants, weighted by their association with Alzheimer's in genome-wide association studies. These scores, particularly when considered alongside APOE status, can help identify people with much higher odds of developing Alzheimer's and earlier onset, and they distinguish cases from controls with AUCs often in the 0.70-0.80 range.
Recent work has expanded PRS into integrative scores that incorporate genetic signals across neurodegenerative, vascular, and metabolic pathways, sometimes using deep-learning methods to capture non-linear effects. In parallel, large plasma proteomic studies and multi-omic analyses (including DNA methylation) have identified protein and molecular signatures that correlate with Alzheimer's pathology and progression. Together, these advances suggest that combining PRS with blood-based proteomic and other "omics" data, plus clinical and digital assessments, could provide a rich picture of near-term risk and disease stage in people who are still functionally normal.
The present study builds on "in silico" (computer-based) modeling work using existing cohorts that already have whole-genome sequencing, plasma proteomics including pTau217, imaging, and longitudinal cognitive and clinical data. Those analyses are being used to develop and calibrate candidate P&R models that estimate the short-term hazard of conversion from cognitively normal or very mildly impaired status to pTau217-positive MCI. The current protocol is a prospective test of one pre-specified P&R model in a new clinical cohort.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 55 years or older at enrollment.
- •APOE Genotype
- •Documented carrier of at least one APOE ε4 allele, based on prior testing (e.g., clinical APOE testing, prior genetic panel, research cohort genotyping, or direct-to-consumer testing).
- •Existing Genomic Data for PRS
- •Whole-genome sequencing (WGS) data already completed, with willingness to provide existing WGS data files (e.g., VCF, FASTQ, or equivalent) to the study team for Alzheimer's disease polygenic risk score (PRS) calculation; or
- •If WGS is not available, prior high-density or targeted genotyping array data covering Alzheimer's disease risk loci, with willingness to provide these data for PRS calculation (feasibility of array-based PRS will be evaluated case-by-case).
- •Note: The study does not perform APOE genotyping or WGS as part of the research; these must be completed before enrollment.
- •Cognitive Status at Baseline
- •Cognitively normal or very mildly impaired at baseline, defined by:
- •Digital cognitive assessment and/or Punto Test consistent with a Global Clinical Dementia Rating (CDR) of 0 or 0.
- •No clinical diagnosis of dementia.
- •For cognitively normal (CN) and subjective cognitive decline (SCD) participants, staging by the Progression and Risk (P&R) model (combining PRS, biomarker, and cognitive data) will be applied for risk stratification.
- •Absence of Baseline AD-MCI by Biomarkers
- •Does not currently qualify for Alzheimer's disease-related MCI (AD-MCI), operationalized as no evidence of MCI with plasma or CSF pTau217 level above a validated cutoff for AD-MCI pathology.
- •Capacity and Participation Ability
- •Able to provide informed consent (with capacity assessments and, where applicable, involvement of a legally authorized representative per institutional policy and IRB approval).
- •Able and willing to comply with study procedures, including clinic visits, cognitive testing, and biospecimen collection.
- •Willingness to Use Digital Monitoring Tools
- •Willing to wear and/or carry digital devices for continuous or frequent monitoring (e.g., smartphone app, wearable sensors such as Oura Ring, sleep device), and to participate in app-based cognitive and speech assessments.
- •Data-Sharing Authorizations
- •Willingness to sign data release authorizations allowing the study to obtain existing genomic data (WGS or array) and relevant electronic medical record (EMR) data needed for risk modeling and outcome adjudication.
排除标准
- •Baseline Dementia Diagnosis
- •Clinical diagnosis of dementia of any cause at baseline.
- •Major Neurological Disorders Affecting Cognition
- •History of major neurological conditions that in the investigator's judgment may confound cognitive assessment or outcomes, such as:
- •Parkinson's disease.
- •Stroke with residual neurological deficits.
- •Epilepsy with frequent seizures.
- •Major Psychiatric Illness
- •Major psychiatric disorders that significantly interfere with participation or data interpretability, such as uncontrolled major depressive disorder or schizophrenia, as judged by the investigator.
- •Serious or Unstable Medical Conditions
- •Uncontrolled systemic medical illness expected to limit life expectancy to less than approximately 3 years, including but not limited to unstable cardiac, hepatic, or renal disease.
- •Recent Investigational or Disease-Modifying AD Treatments
- •Use of investigational drugs or disease-modifying Alzheimer's therapies within 6 months prior to baseline, if such treatments are likely to confound biomarker trajectories or cognitive outcomes.
- •Inability or Unwillingness to Use Required Digital Tools
- •Lack of Required Genomic Documentation or Refusal to Share Data
- •No prior APOE genotype documenting at least one ε4 allele; or
- •No available WGS or suitable genotyping array data; or
- •Refusal to share existing APOE/genomic data and necessary EMR data with the study team.
- •Baseline MCI with Positive pTau217
- •Vulnerable Populations Not Targeted
- •Children, prisoners, and pregnant individuals are not specifically targeted and will be excluded from enrollment.
研究组 & 干预措施
Oura Ring and Apple Kit
Digital Biomarkers
Non Digital Biomarker
Non Digital Biomarker Group
Food for the Brain
Digital Cognitive Screening
Punto Test
Speech Biomarker Screening
No Cognitive Screening
No cognitive Screening performed
结局指标
主要结局
Conversion from Cognitively Normal (CN) pTau217 Negative to pTau217-Positive
时间窗: 0-24 months
Proportion of participants who convert from cognitively normal pTau217 negative status at baseline to pTau217 positive . With plasma pTau217 exceeding a validated cutoff for AD pathology on a clinically validated assay.
次要结局
- Time to Conversion from CN pTau217 negative to pTau217-Positive Status (Biomarker Conversion)(0-24 months)