– NeuroSync

The NeuroSync project aims to investigate how glucose dysregulation contributes to the progression of moderate-to-late-stage dementia. This phase is marked by accelerated patient’s cognitive and functional decline, potential early institutionalization, and shorter survival. Although diabetes is a well-established risk factor for dementia, up until now it has been poorly understood how the specific mechanisms and thresholds of broader glycaemic disturbances, such as insulin resistance and glucose variability, interact with patient genetic, lifestyle, and psychosocial factors and consequently influence disease progression. NeuroSync seeks to address this knowledge gap and translate its findings into personalised, scalable interventions that improve health outcomes for diverse populations who are or will be affected by dementia. The project is structured across three integrated research objectives (RO): RO1 (Phase 1): Predictive Modelling and Causal Analysis. This phase will leverage data from large, ethnically and socioeconomically diverse longitudinal cohorts, including the UK Biobank (discovery) and cohorts such as AgeCoDe/AgeQualiDe, Rotterdam Study, NAKO, and the Three-City Study for validation. The purpose is to develop and validate interpretable machine learning-based predictive algorithms of the progression of dementia and its subtypes including Alzheimer’s and vascular dementia as well as all-cause mortality. These algorithms will incorporate glycaemic markers (e.g., HbA1c, fasting glucose, glucose variability, HOMA-IR as a proxy for insulin resistance), comorbidities, genetic risk (e.g., APOE4), lifestyle, and medication use (e.g., metformin and statins). Causal relationships will be explored using Mendelian Randomisation and mechanistic studies will be employed. Harmonisation across cohorts will be ensured using standard cognitive assessments (e.g., MMSE, MoCA), staging tools (e.g., Clinical Dementia Rating), and biomarker or imaging data, under a unified statistical analysis plan and centralised oversight (work package (WP)2–WP4). This phase will yield a validated predictive prototype to inform personalised interventions in WP5. RO2 (Phase 2): Intervention Co-Design. This phase builds on RO1 to develop a personalised, culturally adapted intervention combining data-driven glucose management with Acceptance and Commitment Therapy (ACT). ACT, effective for health behaviour change, is adapted here for dementia. The intervention includes digital self-help, caregiver support, and Continuous Glucose Monitoring (CGM)-based feedback. It will be co-designed and validated via Delphi panels, expert input, and stakeholder engagement to ensure relevance, sensitivity, and scalability. Outputs feed directly into WP6. RO3 (Phase 3): Feasibility Pilot Study. A single group mixed-methods feasibility study will involve 40 individuals with moderate-to-late-stage dementia and glucose dysregulation. We will test the feasibility and acceptability of this intervention. Feasibility metrics will include both quantitative and qualitative components, examining recruitment and engagement rates and their underlying reasons, as well as caregiver input. Exploratory outcomes will assess emotional wellbeing, cognition, and caregiver burden. RO3 is designed to guide future effectiveness trial refinements and scale-up plannings (WP6).