ALZEVIT: Nationwide Digital APOE ε4 Cohort for Early Alzheimer's Disease Prevention and Trial Readiness

ALZEVIT: A Nationwide Decentralized Digital Cohort for Population APOE Genotyping, Longitudinal Characterization of APOE ε4/ε4 Trajectories, and Trial-readiness for Precision Prevention in Early Alzheimer's Disease

ALZEVIT is a nationwide, decentralized, digital-first cohort study in France designed to establish a large-scale Apolipoprotein E (APOE) genotyping registry and enable precision prevention strategies for Alzheimer's disease (AD). Sponsored by Firalis SA and conducted in collaboration with French memory centers, it addresses the need for early identification of individuals at high genetic risk, particularly APOE ε4 carriers and ε4/ε4 homozygotes, in the context of emerging disease-modifying therapies most effective in preclinical or early disease stages.

Using an online recruitment platform, participants aged ≥45 years provide electronic informed consent and self-collected saliva samples via home collection kits for centralized APOE genotyping using the APO-Easy® assay, compliant with EU IVDR and US FDA requirements. Data are stored in a secure registry compliant with GDPR.

Phase A (0-18 months) will enroll 50,000 participants to determine national APOE genotype distribution, identify high-risk individuals, and evaluate feasibility of large-scale digital genetic screening, with longitudinal online follow-up including cognitive and risk factor assessments.

Phase B (12-24 months) includes detailed phenotyping of ~2,350 selected participants across all APOE genotypes, including ~750 ε4/ε4 homozygotes. Participants undergo clinical evaluation, MRI, cognitive testing, and multi-omics biomarker profiling (genomics, proteomics, metabolomics, environmental exposure), conducted at memory centers or via telemedicine.

The study classifies participants along the cognitive continuum, including cognitively normal individuals, preclinical AD, mild cognitive impairment (MCI), and mild or moderate AD, to identify genotype-specific trajectories and modifiable risk and resilience factors. ALZEVIT aims to establish a scalable national infrastructure linking genetic stratification with longitudinal biomarker and clinical data to support prevention trials, improve understanding of APOE-related heterogeneity, and advance precision medicine for Alzheimer's disease.

ALZEVIT is a nationwide, decentralized, digital-first observational cohort designed to establish a large-scale APOE genotyping registry in France and create a trial-ready infrastructure for precision prevention in Alzheimer's disease (AD). The study is sponsored by Firalis SA and conducted in collaboration with multiple French memory research centers, including the Centres Mémoire de Ressources et de Recherche (CMRR) network and Centres Hospitaliers Universitaires (CHU). The study integrates digital health tools, centralized genetic testing, and longitudinal phenotyping to address the need for early identification and stratification of individuals at risk for late-onset Alzheimer's disease.

Alzheimer's disease is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Recent advances, including disease-modifying therapies such as anti-amyloid monoclonal antibodies, have demonstrated that treatment is most effective when initiated during the earliest stages of disease before extensive neurodegeneration occurs. However, implementation remains limited by safety considerations, including amyloid-related imaging abnormalities (ARIA), substantial infrastructure requirements, and restricted access in many healthcare systems. These challenges highlight the need to identify individuals at elevated risk before symptom onset and to facilitate scalable and ethically appropriate recruitment into prevention trials.

Genetic stratification has emerged as one of the most robust approaches for identifying individuals at increased risk of Alzheimer's disease. Among known genetic factors, APOE ε4 is the strongest common genetic risk allele for late-onset Alzheimer's disease and is associated with increased amyloid deposition, tau pathology, neuroinflammation, lipid dysregulation, and earlier disease onset. APOE ε4/ε4 homozygotes represent a particularly high-risk subgroup with earlier biomarker changes and accelerated cognitive decline. Although they comprise approximately 1.5% to 2.5% of the general population, they account for a disproportionately large proportion of Alzheimer's disease cases. Conversely, APOE ε2 is associated with reduced risk, and APOE ε2/ε2 homozygosity represents a model of resilience. Emerging evidence supports classification of APOE ε4/ε4 homozygosity as a distinct genetic subtype of Alzheimer's disease characterized by specific biological trajectories and early amyloid accumulation.

The therapeutic landscape for Alzheimer's disease continues to evolve, with investigational therapies targeting multiple biological pathways, including synaptic resilience, cellular stress responses, autophagy modulation, and APOE-directed interventions. This evolving landscape reinforces the need for genetically and biologically stratified populations to support precision prevention and treatment. Consequently, well-characterized longitudinal cohorts are becoming essential infrastructure for future clinical research.

Within this context, ALZEVIT is designed as a scalable national platform enabling population-level APOE genotyping and longitudinal characterization of cognitive, clinical, and biological trajectories. Participants enroll online, provide electronic informed consent, and receive ORAcollect® Dx saliva collection kits. Samples are returned to a centralized laboratory for APOE genotyping using the APO-Easy® assay, a European Union In Vitro Diagnostic Regulation (IVDR)- and United States Food and Drug Administration (FDA)-compliant diagnostic platform with high concordance to sequencing methods.

Phase A (Months 0-18) aims to enroll 50,000 adults aged 45 years and older across France. Participants are stratified into five age groups (45-54, 55-64, 65-74, 75-84, and 85 years or older) to estimate age-specific genotype frequencies. The primary objectives are to determine the national distribution of APOE genotypes, establish a secure General Data Protection Regulation (GDPR)-compliant registry, identify individuals at highest genetic risk, particularly APOE ε4/ε4 homozygotes, and evaluate the feasibility and scalability of decentralized digital genetic screening.

Participants provide self-reported information on demographics, family history of dementia, vascular and metabolic risk factors including hypertension, diabetes mellitus, dyslipidemia, and body mass index (BMI), lifestyle factors including physical activity, diet, smoking, alcohol consumption, sleep quality, mood, hearing status, and medication use. Participants also complete validated cognitive assessments and questionnaires assessing subjective cognitive decline. Periodic remote follow-up assessments monitor cognitive changes and risk factor evolution.

The registry is intended to serve as a national infrastructure for Alzheimer's disease prevention research by supporting longitudinal follow-up, facilitating recruitment into prevention trials, and providing evidence regarding genotype-specific disease trajectories.

Phase B (Months 12-24) includes comprehensive phenotyping of approximately 2,350 participants representing all APOE genotypes, including approximately 750 APOE ε4/ε4 homozygotes. Participants undergo clinical evaluations, standardized neuropsychological testing, magnetic resonance imaging (MRI), and biomarker assessments at participating memory centers or through telemedicine.

Neuropsychological testing includes the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and digital cognitive batteries. Core Alzheimer's disease biomarkers, including amyloid-beta peptide 40 (Aβ40), amyloid-beta peptide 42 (Aβ42), phosphorylated tau 217 (p-tau217), phosphorylated tau 181 (p-tau181), and total tau, are measured using validated in vitro diagnostic (IVD) platforms. Additional genetic analyses are performed using extended neurodegeneration gene panels. Participants are classified as cognitively normal, having preclinical Alzheimer's disease, having Mild Cognitive Impairment due to Alzheimer's disease, or having mild to moderate Alzheimer's disease.

A major component of Phase B is integrated multi-omics and environmental exposure profiling. Saliva, whole blood, serum, plasma, and urine samples are collected and stored in a biobank certified according to International Organization for Standardization (ISO) 20387. Analyses include genomic, transcriptomic, proteomic, metabolomic, and environmental exposure analyses to identify biological pathways and biomarkers associated with disease onset and progression.

The study also evaluates modifiable risk and resilience factors, including cardiovascular and metabolic health, physical activity, sleep, dietary habits, mood, anxiety symptoms, social engagement, hearing impairment, and medication use. These variables will be examined in relation to cognitive trajectories, biomarker evolution, and clinical progression.

Comparative analyses across APOE genotypes are central to the study design. APOE ε4/ε4 homozygotes will be compared with other genotype groups to characterize differences in biomarker profiles, neuroimaging findings, and cognitive trajectories across age groups. These analyses aim to improve understanding of APOE ε4/ε4 as a distinct genetic subtype of Alzheimer's disease and to inform future population screening strategies.

Operationally, ALZEVIT will evaluate the feasibility of large-scale decentralized neurological research, including recruitment efficiency, participant adherence, sample return rates, data completeness, and the quality of remotely collected genetic and clinical data. Hybrid approaches combining digital follow-up with targeted in-person assessments will also be evaluated.

Ethical oversight includes compliance with the General Data Protection Regulation (GDPR), implementation of data minimization principles, independent data protection monitoring, and secure management of genetic information. Participants retain full informed consent rights, and study data are used only for approved research purposes.

ALZEVIT is intended to establish a national infrastructure supporting Alzheimer's disease prevention and precision medicine by integrating population-scale APOE genotyping with longitudinal cognitive, clinical, and biomarker data. The study is expected to facilitate recruitment into prevention and early intervention trials, improve understanding of genotype-specific disease trajectories, support personalized risk prediction, and contribute to strategies that reduce the future burden of Alzheimer's disease.

Inclusion Criteria:

• Participants who sign the electronic Informed Consent form.
• Adults aged over 45 years old (inclusive) at the time of consent.
• Participants residing in France.
• Participants able to read and understand the study information in French or with the help of a legal representative.
• Participants are capable of electronically signing the consent form.
• Participants affiliated with the French national health insurance system.
• Participants with access to the internet and a valid email address.
• Participants can self-collect and return a saliva sample using a provided kit (ORAcollect® Dx device).

Exclusion Criteria:

• Participants who do not sign the Informed Consent form.
• Participants who are unable to read or understand French.
• Participants younger than 45 years at the time of consent.
• Participants with known cognitive impairments, severe dementia, or psychiatric conditions that prevent informed consent.
• Participants with a documented substance use disorder (alcohol or drug dependence) within the past 24 months.
• Participants who cannot be reliably contacted by email or phone.
• Participants previously enrolled in the ALZEVIT study or its pilot phase.
• Participants who are legally protected adults or under guardianship, curatorship, or judicial/administrative custody.
• Participants whose physical condition does not allow them to perform the tasks required by the study.
• Participants who, in the judgment of the Investigator, are unlikely to comply with study procedures.
• Participants who are study staff (investigators, sub-investigators, coordinators, assistants) or their immediate family members.
• Participants who are incarcerated or deprived of liberty by judicial or administrative decision.
• Participants with any disease or condition that, in the opinion of the Investigator, would compromise participation or safety.