Predicting Pre-dementia

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.

Overall goals and main questions This study's overarching aim is to validate a fixed proteogenomic P\&R model in a real-world group of ApoE4-positive older adults and to assess whether such a model can feasibly be implemented using a combination of existing genomic data, blood tests, and scalable digital monitoring.

For a broad audience, the main questions the study asks are:

Among ApoE4-positive adults aged 55 and older who are cognitively normal or only very mildly impaired at the start of the study, how well does a pre-specified P\&R model distinguish those who will convert to early, pTau217-positive MCI Stage I within 24 months from those who will not convert during that time?

How practical and acceptable is it to carry out this kind of multimodal assessment-combining existing genetic data, repeated blood tests, digital cognitive and speech measures, and continuous wearable monitoring-over a two-year period in this population?

How does the performance of the full P\&R model compare with simpler approaches, such as models based only on APOE plus PRS or standard clinical and cognitive measures, when predicting early MCI due to Alzheimer's?

Do digital and wearable measures (such as Oura Ring-derived sleep and activity metrics, brief speech features, and app-based cognitive tasks) meaningfully improve prediction beyond what can be achieved with genetic, blood-based, and traditional clinical measures alone?

What are the practical costs and logistics of different sampling strategies (for example, venous vs fingerstick blood, more in-person visits vs more remote monitoring), and how do these relate to the number of true conversion events correctly identified?

Secondary and exploratory goals include estimating short-term (2-5-year) and modeled longer-term (up to 10-year) conversion probabilities from cognitively normal status to MCI in this enriched, higher-risk population, and examining how an Oura Ring-based exposome risk score relates to proteogenomic risk scores and cognitive-functional measures.

Study design in plain language This is a longitudinal observational cohort study: researchers observe and measure participants over time without giving any experimental drugs or devices. The cohort will include up to roughly 90 ApoE4-positive adults at first, with plans to expand toward 100 participants as the study matures; participants are at least 55 years old and either cognitively normal or only very mildly impaired at baseline.

The study follow-up lasts 24 months from the baseline visit. Each participant attends in-person clinic visits at baseline (month 0) and at months 6, 12, 18, and 24, with an allowable window of about two months around each follow-up. Between visits, participants are monitored continuously or frequently through digital tools, including an Oura Ring and a smartphone app, to track sleep, physical activity, heart rate metrics, mobility and location, and short digital cognitive or speech tasks. A subset of about ten participants will have especially intensive wearable monitoring.

No experimental treatment is given. Instead, the focus is on gathering detailed data-genetic, blood-based, cognitive, and digital-from a well-characterized, higher-risk group in order to apply and test the P\&R model. If participants meet criteria for MCI with positive Alzheimer's biomarkers (for example, if pTau217 becomes elevated), they are referred to a neurologist, and they may be discharged from the study once they are considered "MCI positive."

Who can take part? The target population consists of adults who already know they carry at least one copy of the ApoE4 variant and have existing genomic data from earlier testing. These people may come from prior clinical care, previous research studies, or commercial direct-to-consumer genetic services, but they must be willing to share their data with the study.

Key inclusion criteria:

Age 55 or older at enrollment.

At least one ApoE4 allele documented by prior testing (for example, clinical ApoE testing, a genetic panel, or research genotyping).

Whole-genome sequencing (WGS) or, if WGS is not available, a high-density genotyping array covering Alzheimer's risk loci, with willingness to provide the raw data files (e.g., VCF, FASTQ) for PRS calculation.

Cognitively normal or very mildly impaired at baseline, as judged by digital cognitive testing and standardized scales (global CDR 0 or 0.5, no diagnosis of dementia).

For cognitively normal (CN) and subjective cognitive decline (SCD) participants, the P\&R model staging criteria-which combine PRS, biomarker, and cognitive data-will be applied to assign risk levels.

Ability to provide informed consent and to comply with study procedures.

Willingness to use digital devices (such as a smartphone, wearable sensors, and a sleep device like the Oura Ring) for continuous or frequent monitoring.

Important notes for potential participants:

The study does not perform ApoE genotyping or whole-genome sequencing as part of the research; these must already have been done before enrollment.

People without documented ApoE4 carrier status, or without available genomic data suitable for PRS calculation, are not eligible.

Exclusion criteria include:

A diagnosis of dementia (of any cause) at baseline.

Major neurological conditions that could interfere with cognitive assessment, such as Parkinson's disease, stroke with ongoing deficits, or frequent seizures.

Major psychiatric illness (for example, uncontrolled major depression or schizophrenia) that would interfere with participation or interpretation of data.

Serious uncontrolled medical illness (such as unstable heart, liver, or kidney disease) likely to limit life expectancy to less than about three years.

Use of investigational drugs or disease-modifying Alzheimer's therapies within the previous six months, if these could alter biomarker trajectories.

Contraindications to optional procedures like EEG, MRI, or PET scans (for example, certain implanted devices or severe claustrophobia).

Inability or unwillingness to use required digital monitoring tools, such as lack of smartphone access or severe sensory impairments that prevent use.

Refusal to share existing ApoE/genomic data or electronic medical record (EMR) information as needed for the study.

Participants who at screening already meet criteria for MCI with elevated pTau217 (that is, biomarker-positive MCI due to Alzheimer's) will not continue in the study and will instead be referred to a neurologist.

The initial plan is to start with a small "vanguard" group of about ten participants who already use Oura Rings, then gradually expand to a total of around 100 participants over time, with roughly equal representation across low, average, and high PRS categories among cognitively normal ApoE4 carriers.

What is the P\&R model and PRS? The polygenic risk score (PRS) used in this study is derived from genome-wide data using effect sizes from large, well-validated Alzheimer's GWAS and meta-analyses. To avoid double-counting, the APOE region is excluded from the PRS, and APOE genotype (such as number of ApoE4 alleles) is modeled separately as its own predictor.

• Time to Conversion from CN pTau217 negative to pTau217-Positive Status (Biomarker Conversion) [Time frame: 0-24 months]