Abstract Diffuse white matter disease (DWD) is a common manifestation of small-vessel cerebrovascular pathology and a key subtype of vascular contributions to cognitive impairment and dementia (VCID). However, the mechanistic underpinnings of DWD remain incompletely characterized. Based on assessment of extensive data in humans and animal models, we have identified angiogenic mediators, in particular placental growth factor (PlGF), as being strongly associated with diffuse white matter disease. Much like the pathologic angiogenesis that occurs in retinopathies, pathologic angiogenesis in the brain results in blood-brain barrier leakage and, counterintuitively, tissue ischemia. We have exciting preliminary data indicating robust relationships between PlGF and human DWD. We have also identified PlGF as being increased in association with blood-brain barrier leakage. We hypothesize that PlGF, and related angiogenic mediators, result in pathologic angiogenesis, with leaky, tortuous vessels and surrounding inflammation, leading to diffuse white matter disease. Importantly, these pathologic changes also represent a potentially targetable mechanism to improve cognition in aging. To test these hypotheses, we propose focused studies in an extensively characterized human cohort, and a mouse model of small vessel disease. We answer the “what, where, why” questions surrounding PlGF. “What” cell type is responsible for PlGF; “where” is PlGF being expressed; “why” is PlGF upregulated and can it be modulated. To test these hypotheses, we propose focused studies in an extensively characterized human autopsy cohort, and a mouse model of small vessel disease: Specific Aim 1: Determine contributions to plasma PLGF, and related angiogenic proteins, using cell- specific exosomes and their association with periventricular and deep white matter pathologies. Specific Aim 2: Ascertain the regional expression of PLGF, and related angiogenic proteins, within, adjacent to, and distant from, periventricular and DWD and the association with aberrant angiogenesis. Specific Aim 3: Test the potential to manipulate PLGF related small vessel pathology in response to hyperhomocysteinemia (HHcy)-induced small vessel disease.