Heterogeneous vascular contributions to cognitive impairment and dementia.

Vascular cognitive impairment and dementia (VCID) is an umbrella term that covers a spectrum of cerebrovascular pathologies culminating in cognitive decline. As such, there is no single clinical diagnosis of VCID and no single mechanism underlying the different forms of VCID. Different subtypes of VCID differ in etiology, risk factors, pathophysiological mechanisms, brain pathology and clinical presentation. In contrast to the increasing recognition of VCID heterogeneity in the clinical setting, the preclinical literature continues to treat VCID animal models as a homogeneous group, failing to align them with specific clinical phenotypes. Similarly, current VCID markers represent late-stage pathological processes and tissue damage that are common among all forms of cerebrovascular pathologies and do not distinguish between different VCID subtypes. Here, we adopt a classification of VCID based on etiology and affected vascular segments, organizing animal models according to these subtypes, and proposing to assign VCID biomarkers within these categories. We argue this approach better represents the heterogeneity of clinical VCID risk profiles, mechanisms and presentations, which not only improves understanding of VCID, but may also accelerate the discovery of early subtype-specific biomarkers and mechanism-based and disease-modifying VCID therapies.