From mechanism to intervention: lipoproteins and Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is the leading global cause of dementia, characterized by memory impairment and neuropathological hallmarks of amyloid and tau deposition. Several cardiovascular risk factors, including hypertension, type II diabetes, and dyslipidemia, are modifiable risk factors of AD, especially during midlife, highlighting a close interplay between AD and vascular contributions to cognitive impairment and dementia (VCID). The objectives of this narrative review are to: (1) synthesize recent literature, mainly from 2024 to 2026, on how lipoproteins, namely apolipoprotein E (ApoE), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), influence risk of AD and related dementias (ADRD), (2) describe mechanisms by which lipoproteins may contribute to ADRD and VCID risk, and (3) highlight potential interventions that involve lipoprotein metabolism with a focus on cholesteryl ester transfer protein (CETP), which regulates LDL-C and HDL-C levels in humans. Interest in CETP as a potential therapeutic target in dementia is surging, as a new and well-tolerated CETP inhibitor obicetrapib was recently found to slow progression of plasma p-tau-217, an approved diagnostic biomarker of amyloid positivity, over 12 months of treatment in patients with atherosclerotic cardiovascular disease, with more pronounced effects in APOE4 carriers.