PCSK9 in Brain Health and Disease: Liver-Vascular-Brain Interactions in Aging and Disease

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of peripheral cholesterol metabolism. Inhibitors of hepatic PCSK9 potently reduce low-density lipoprotein cholesterol (LDL-C) and have become a staple of lipid-lowering therapeutic regimens for patients with atherosclerotic cardiovascular disease. Although the role of PCSK9 in the central nervous system (CNS) is less well-defined, accumulating evidence suggests that it modulates CNS cholesterol homeostasis and responses to injury, neuroinflammation, and amyloid-β and tau protein deposition. Thus, peripheral and central PCSK9 molecular actions have important pathophysiological consequences for aging, cerebrovascular disease, and neurodegenerative disease. In this review, we summarize PCSK9 functions in the context of the liver-vascular-brain axis and examine mechanistic and therapeutic links in PCSK9 biology and neurological diseases. By integrating insights from preclinical and clinical research, we highlight the current state of knowledge regarding the potential relevance of PCSK9-inhibiting therapies in brain health and disease. Given the remarkable lipid-lowering effects of PCSK9 inhibitors, advancing our understanding of the multi-organ interactions influenced by PCSK9 may inform future therapeutic strategies, although clinical evidence supporting neurological benefit currently remains limited.