1 Department of physics, Concordia University, 7141 Rue Sherbrooke, Montreal, QC, Canada; Centre de Recherche de l'Institut de Cardiologie de Montréal, 5000 Rue Belanger, Montreal, QC, Canada.
2 Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, ON, Canada.
3 Department of Radiology, University of Sherbrooke, 2500 Bd de l'Université, Sherbrooke, QC, Canada.
4 Douglas Mental Health Institute, 6875 Boul. LaSalle, Montreal, QC, Canada; STOP-AD Centre, 6875 Boul. LaSalle, Montreal, QC, Canada; Department of Psychiatry, Faculty of Medicine, McGill University, 845 Rue Sherbrooke, Montreal, QC, Canada.
5 Department of Neurology & Neurosurgery, McConnell Brain Imaging Centre, Montreal Neurological Institute, 3801 Rue University, Montreal, QC, Canada; Ludmer Centre for Neuroinformatics and Mental Health, 1010 Rue Sherbrooke, Montreal, QC, Canada.
6 Department of physics, Concordia University, 7141 Rue Sherbrooke, Montreal, QC, Canada; Centre de Recherche de l'Ins

Alzheimer's disease (AD) is a complex disease that involves complex interactions between protein biomarkers such as amyloid beta (Aß) and tau, neurodegeneration, cerebrovascular health and inflammation. However, how these factors interact, especially in the early phases of disease development remain unclear. To address this, this study analyzed four-year longitudinal data from 110 cognitively unimpaired older adults with a family history of AD in the PreventAD cohort. We investigated relationships between CSF Aß, 181-phosphorylated tau (p-tau), interleukin-8 (IL-8), cerebral blood flow (CBF), and grey matter volume (GMV) in groups with high and low cardiovascular risk levels. Longitudinally, lower CSF Aß within participants (a proxy for higher brain amyloid) was linked to a slower decline in regional CBF, particularly in those with higher cardiovascular risk. Similarly, in the high vascular risk group, higher IL-8 at baseline was associated with greater decline in CBF in the right superior temporal gyrus. Further, lower baseline CBF was associated with greater CSF p-tau accumulation over time. Finally, higher baseline CSF p-tau was associated with faster GM atrophy over 4 years, particularly in the hippocampus. Our results highlight the complex interactions between CSF misfolded proteins, inflammatory markers, and brain regional CBF and atrophy, and how these effects are more pronounced in individuals with higher vascular risk factor load. These findings demonstrate the need for comprehensive models of AD pathophysiology that integrate vascular health and inflammation measures alongside traditional biomarkers.