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Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts (n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia. Editor's summary: Aberrant angiogenesis may contribute to brain aging in humans, but supporting data are limited. Here, Torres-Espin and colleagues applied machine learning and linear mixed effects models to longitudinal data from deeply phenotyped cohorts of aging participants to evaluate the relationships between markers of angiogenesis and structural and functional readouts of brain aging. Concentrations of angiogenesis markers were associated with brain health, with sex-dependent or dimorphic patterns observed, as well as age-dependent directionality. Two principal components were identified, named aberrant angiogenesis and vascular health, and selected angiogenesis markers contributing to these components were noted. These findings, which were broadly validated in a small independent cohort, highlight the association of angiogenesis factors with brain aging and the effects of sex on these interactions, which will need to be explored in future studies. —Melissa L. Norton [ABSTRACT FROM AUTHOR]