Weili Xu

Dementia remains a major public health challenge, with no cure available. Metformin, a widely prescribed medication for type 2 diabetes (T2D), has attracted interest for its potential neuroprotective effects, though its impact on cognitive health remains unclear. This five-year project investigates Metformin’s role in cognitive aging—spanning cognitive decline, cognitive impairment and dementia—while exploring its mechanisms in brain aging.We aim to: Examine associations between Metformin use, cognitive aging, and brain measures in people with T2D compared to other glucose-lowering therapies. Unravel target-specific effects on brain aging using drug-target Mendelian Randomisation. Investigate neuroplastic changes through an intervention study. Develop personalized clinical criteria to estimate Metformin’s effects on brain aging.To achieve our objectives, we will utilize data from four population-based cohorts and a quality register: the Swedish National Study on Aging and Care-Kungsholmen (n=3,363), the Screening Across the Lifespan Twin Study (n=44,919), the UK Biobank (n=502,412), the Memory and Aging Project (n=2,192), and the Swedish Dementia Register (n=129,387). We will also conduct an intervention study (n=120).With comprehensive data on drug use, cognitive tests, imaging, biomarkers, health status, and lifestyle, this project could provide critical insights into Metformin´s effects on brain aging, paving the way for novel dementia treatments and prevention strategies.

Depression is a leading cause of disability worldwide, yet its clinical management remains suboptimal due to its marked heterogeneity. Research in both humans and animal models has identified key neurocognitive dimensions relevant to depression. We have developed a novel set of cognitive tests to assess these dimensions. In this project, we will administer these tests online to a large sample of patients receiving specialized psychiatric care, as well as to a comparison group of adults without psychiatric history. Using normative modeling, we will quantify how much each patient deviates from the non-psychiatric norm. These cognitive deviations will be used to predict clinical outcomes via linkage to the National Registers and to identify clinically meaningful subtypes. Additionally, we will test preadolescent children—before the typical rise in depression onset—to detect early cognitive markers associated with later risk. Normative modeling will help us identify deviations from typical development that may signal vulnerability. This project has the potential to transform depression care through a transdiagnostic, precision medicine approach and to support early preventive interventions in children at risk.

Research Problem and QuestionsDementia presents a significant challenge to healthcare systems. The complex nature of the condition requires individuals and their caregivers to engage with multiple healthcare sectors, necessitating coordinated, person-centred care across various providers. However, several barriers impede the effective delivery of holistic care. As a result, the urgent need for coordinated, person-centred care for individuals with dementia remains largely unmet.This project aims to address these challenges by focusing on the intersections and collaboration across systems, ultimately providing practical recommendations to support coordinated and person-centred care for people with dementia. The specific questions we aim to address are: 1) To what extent does care fragmentation occur among people with dementia? 2) What are the volume and trajectory of care transitions among patients with dementia? 3) What are the unmet needs and potential solutions for coordinated, person-centred dementia care?Data and MethodsThis project will adopt an innovative approach from observation to implementation, by leveraging data from the Swedish National Study on Aging and Care in Nordanstig (SNAC-N, n=766), the Screening Across the Lifespan Twin Study (SALT, n=44,919), and the National Swedish Register for Cognitive/Dementia Disorders (SveDem, n=129,387). Additionally, we will conduct qualitative studies further to understand dementia care and the well-being of caregivers.Societal Relevance and UtilisationDementia care in Sweden has faced criticism for structural deficiencies, such as fragmentation and poor coordination. There is limited knowledge about how different care providers coordinate in practice. This project aims to enhance our understanding of how collaboration in dementia care occurs and how it is experienced by various care providers. A comprehensive investigation of these issues is essential for optimizing the dementia care process and establishing an effective model for care collaboration.Plan for Project RealisationThe project is grounded in well-established cohort studies and an extensive dementia registry that encompasses both specialist and primary care at national and regional levels. These are complemented by qualitative studies involving patients with dementia and their caregivers. Through the collaborative efforts of a multidisciplinary team, this project offers a unique opportunity to address significant knowledge gaps in dementia care.