Abstract
INTRODUCTION: Intracranial atherosclerotic disease (ICAD) of the large cerebral arteries, a leading cause of stroke worldwide, is increasingly implicated in cognitive impairment and neurodegeneration among the general population; however, the underlying pathophysiologic mechanisms in this relationship remain unknown. METHODS: In this narrative review, we aim to provide an overview of the epidemiology and pathophysiology of ICAD, the evidence that relates ICAD to neurodegeneration, putative mechanisms, and future research directions. We synthesized available evidence on PubMed up to August 2024. RESULTS AND CONCLUSIONS: ICAD, a common cause of stroke, is characterized as a chronic, inflammatory, fibroproliferative disease of the cerebral large arteries. Numerous lines of evidence have related ICAD to clinical, neuroimaging, and pathology-based markers of cognitive impairment and Alzheimer's disease; however, little data exists on plausible pathophysiological links. Based on ongoing and adjacent work, we hypothesize hypoperfusion, arterial stiffness, and inflammation to play a role, but further research is needed. Conventional classification of ICAD often infers from symptomatic coronary artery disease and relies on degree of luminal stenosis, but unique anatomic features of the intracranial circulation may be relevant and a more comprehensive description that includes arterial wall features and plaque morphology may be needed to fully understand its relationship with cognitive impairment and neurodegeneration.