High-Density Lipoprotein Changes in Alzheimer’s Disease Are APOE Genotype-Specific

Abstract

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function.

DiLeu Isobaric Labeling Coupled with Limited Proteolysis Mass Spectrometry for High-Throughput Profiling of Protein Structural Changes in Alzheimer’s Disease

“…HPTR, as a primate-specific plasma protein, is associated with apolipoprotein L-I (apoL-I)-containing high-density lipoprotein (HDL) . Different studies from human, animal models, and bioengineered arteries confirmed that HDL protects against cerebrovascular dysfunction in AD. − FA12 is a serum glycoprotein that participates in misfolded protein binding, but no direct evidence of a specific role for FA12 in AD has been reported.…”

APOE3-R136Smutation confers resilience against tau pathology via cGAS-STING-IFN inhibition

“…Increased systemic APOE levels have also been observed in carriers of the protective APOE2 isoform 15,29 while low levels of APOE have been associated with amyloid pathology and mild cognitive impairment in the clinic 30 . Furthermore, APOE isoforms have been shown to alter several of its functional characteristics such as HDL particle size, cholesterol efflux capacity, and acetyltransferase activity 31 . However, unlike Chen et al, which reported elevated plasma APOE levels in E3 S/S mice, we observed similar APOE levels in E3 and E3 S/S mice in plasma.…”

Association Between Fluctuations in Blood Lipid Levels Over Time With Incident Alzheimer Disease and Alzheimer Disease–Related Dementias

“…31 HDL-C and HDL-C variations relationship to AD/ADRD may be dependent on APOE haplotypes; however, our study did not have access to this information. 32 APOE, specifically APOE e4 allele, has long been known to significantly increase the risk of late-onset AD because of its role in lipid homeostasis. 33 APOE has been shown to modulate the impact of cerebrovascular risk factors on the AD risk.…”

“…31 HDL-C and HDL-C variations relationship to AD/ADRD may be dependent on APOE haplotypes; however, our study did not have access to this information. 32…”