Factor analysis of multimodal MRI, biofluid, and vascular biomarkers reveals latent constructs of brain health.

Individual imaging and fluid biomarkers provide insights into specific components of brain health, but integrated multimodal approaches are necessary to capture the complex, interrelated biological systems that contribute to brain homeostasis and neurodegenerative disease. Using data from the Brain and Cognitive Health (BACH) cohort study (N = 127; mean age = 67 years, 68% women), we performed an exploratory factor analysis to identify latent constructs of brain health. We included multimodal neurovascular imaging markers, brain atrophy metrics, plasma Alzheimer's disease (AD) biomarkers, and cardiovascular risk factors. Five constructs emerged: "Brain & Vascular Health" (greater hippocampal volume, basal ganglia enlarged perivascular spaces (ePVS), cerebral blood flow, and HDL cholesterol; lower ventricle volume and BMI), "Structural Integrity" (greater cortical thickness, fractional anisotropy, and basal ganglia ePVS), "White Matter (WM) Fluid Dysregulation" (greater WM ePVS and Free Water), "AD Biomarkers" (higher phosphorylated tau [pTau]181 and pTau217; lower amyloid-beta 42/40 ratio), and "Neuronal Injury" (higher glial fibrillary acidic protein and neurofilament light chain). All constructs were associated with age (β = - 0.70-0.39, p ≤ 0.014), except for WM Fluid Dysregulation (p > 0.05). Brain and Vascular Health and Structural Integrity (partial r = 0.305, p < 0.001) and AD biomarkers and neuronal injury (partial r = 0.248, p = 0.005) were positively correlated. Only Brain and Vascular Health was associated with global cognition (β = 0.27, SE = 0.13, p = 0.043). These findings provide a data-driven framework for examining distinct constructs underlying vascular health, fluid regulation, and neurodegenerative pathology. We demonstrate the utility of using multiple biomarkers to probe these biological systems, paving the way for future research to explore how these systems change across diverse neurodegenerative conditions.