Linking modifiable risk factors to vascular and neurodegenerative brain changes.

Dementia reflects vascular and neurodegenerative processes in late life, yet studies often examine risks and outcomes individually. This study tested whether the cumulative burden of risks relate to vascular brain injury and cognitive performance and whether brain markers are associated with part of these associations through cross-sectional indirect pathways. Cross-sectional data were drawn from 38,414 older adults in the National Alzheimer's Coordinating Center database. A composite index summed ten binary risk factors: hypertension, diabetes, hypercholesterolemia, alcohol misuse, smoking, depression, obesity, hearing loss, vision loss, and low education. Outcomes included white matter hyperintensities (WMHs), infarcts, hippocampal atrophy, global cognition, cognitive status, delayed recall, and semantic fluency. Higher cumulative risk burden was associated with poorer cognitive outcomes and greater structural brain injury. Each additional risk factor was linked to worse global cognitive status, greater clinical severity, lower delayed recall, lower semantic fluency, and higher odds of WMHs, cerebral infarcts, and hippocampal atrophy. Hippocampal atrophy demonstrated the largest indirect pathway among the evaluated MRI markers, whereas WMHs and infarcts showed smaller indirect pathways. The findings suggest that cumulative modifiable risk burden is associated with poorer brain health and cognitive functioning in later life. Examining risk factors collectively provides a clearer understanding of brain health vulnerability and supports multidomain prevention strategies that target clustered modifiable risks.