HDL and Alzheimer’s disease: recent advances and therapeutic implications

Abstract High-density lipoproteins (HDL) belong to a group of lipid-protein complexes that are assembled in extracellular space and circulate as soluble nanoparticles in biological fluids, transporting lipids and associated molecules from and to cells throughout the body. Although discovered first, HDL remains to be the least understood among all lipoproteins. While initially studied primarily in the systemic circulation, interest in HDL-like particles in the brain has grown following the discovery of the HDL-associated apolipoprotein APOE4 as the greatest genetic risk factor for late-onset sporadic Alzheimer’s disease (AD), linking HDL with neurodegeneration as well as cardiovascular disease. This review aims to summarize growing lines of evidence that demonstrate the roles of HDL and HDL-like particles in multiple interconnected processes implicated in AD pathophysiology, including amyloid and tau pathology, neuroinflammation, mitochondrial function, cerebrovascular integrity, lipid metabolism, and synaptic function, as well as underscoring the paradigm shift from HDL levels to HDL function. In addition, this review highlights the potential of emerging HDL-targeted interventions for AD and discusses future research directions.