Anna Marseglia

Vascular Cognitive Impairment (VCI) due to cerebrovascular disease—dementia leading cause—is underdiagnosed and poorly understood due to lack of diagnostic criteria and fragmented mechanistic insights. I will uncover health behaviours and biological processes linking inflammation, glucose and lipid metabolism to small vessel disease (SVD) and VCI. My team will: Characterize the natural history of VCI, implementing new diagnostic criteria to identify key transition driversDefine mechanistic pathways linking inflammation and metabolism to SVD and VCI (biosignatures)Determine how a multimodal lifestyle intervention preserves cognition (resilience) despite SVD by modifying transition drivers, biosignatures, or bothBy the project’s end, I will identify biomarkers for early VCI detection and actionable targets for tailored interventions. This will refine risk assessment tools and inform clinical trials and healthcare strategies for effective, person-cantered VCI prevention.We will integrate neuroimaging, clinical, sociobehavioral, and proteomic data—alongside an AI-based resilience measure, the Brain Age Gap—from the H70 and UK Biobank cohorts and the FINGER trial. Using modern statistical methods (eg mixed-effect, multi-state models, random forests), we will achieve our goal within 4 yrs (Yr-1 Aim1

Yr-2 Aim2

Yr-3&4 Aim3). My multidisciplinary team (epidemiology, neuroimaging, geriatrics, statistics) and established resources at NVS,KI provide a strong foundation for success.

Research problem and specific questions Dementia poses a major public health challenge with no cure, underscoring the need for prevention by tackling risk/protective factors like social health (SH

the ability to engage meaningfully, maintain supportive relationships, and feel belonging within one´s community). Yet, studies often lacked a comprehensive SH framework bridging social and biological dimensions in linking SH and cognitive health and overlooked sex differences. Our project goal is to determine how SH influences cognition leveraging resilience mechanisms across the lifespan, considering factors related to women´s health and sociocultural aspects. This goal will be achieved through 3 research lines (RL) built on a novel conceptual framework from the European SHARED consortium, supported by FORTE. RL1 will investigate the impact of SH, from mid- to late-life, on cognition before dementia manifests, the role of multimorbid disorders and stress. RL2 will investigate how SH contributes to preserving brain integrity (brain maintenance, BM) and/or cognition amid neuropathological changes (cognitive reserve, CR). RL3 will investigate the role of sex differences in the SH-resilience relationship, focusing on sex-specific biological (e.g., hormones-related) and socio-cultural determinants.Data and method We will integrate longitudinal sociobehavioural data with clinical, brain imaging, and women’s health data from the Swedish Betula project (n=4,425, 53% women

age 25-95 yrs

25-yr follow-up). We will validate our results externally using the UK Biobank (n=~500,000, 54% women

age 40-69 yrs

10-yr follow-up). We will generate biological measures of BM and CR using our in-house artificial intelligence algorithm enable to predict the age of the brain from neuroimaging. Plan for project realisation This 3-year project will be conducted by a research team, which brings together expertise in geriatric epidemiology, psychology, medical sociology, neuroscience, and engineering. Design and methodological aspects are discussed in details in the next sections. We plan to disseminate our findings also outside the scientific community by engaging with local and national end-users. Relevance Our findings will assist clinicians/public health professionals in crafting tailored risk reduction strategies/interventions against dementia for both women and men. Targeting specific SH aspects can enhance cognition before dementia symptoms manifest, across relevant life periods.