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 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.