Brain health in Atherosclerosis and Cardiovascular risk in mid-life, a PESA-Brain project

This project aims to investigate the early associations between cardiovascular health and Alzheimers disease (AD) pathology, with a focus on subclinical atherosclerosis (SCAth) and cardiovascular risk factors (CVRFs), in a large cohort of asymptomatic, middle-aged individuals.

The overarching objective is to determine how cardiovascular health in subclinical stages influences both cerebrovascular integrity and early AD biomarkers, and to examine how these factors contribute to cognitive decline, with particular emphasis on sex-specific differences.The proposed research leverages data from the PESA-Brain study, a deeply phenotyped cohort integrating advanced neuroimaging and cognitive testing, with longitudinal cardiovascular and blood-based biomarkers assessments.

We will first test the relationships between cardiovascular health markers and cerebrovascular health, focusing on brain perfusion, microstructure, and microinfarcts.

We will then explore the links between cardiovascular health and AD pathology, using plasma and brain amyloid and tau biomarkers, as well as cognitive outcomes, including memory and executive function.The project will employ advanced statistical approaches, such as linear mixed models and mediation analysis, to handle the complexity of multimodal data and examine causal relationships between cardiovascular health, brain pathology, and cognition.

By including sex-stratified analyses, the research will provide critical insights into gender-specific susceptibilities, which have been underexplored in previous studies.The relevance of this project to the work programme lies in its potential to shift the focus of AD prevention to midlife, offering novel insights into the neurobiological pathways that link cardiovascular dysfunction and neurodegeneration.

These findings could pave the way for earlier interventions targeting modifiable CVRFs, significantly reducing the incidence and societal burden of dementia in aging populations.