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Background: High-density lipoprotein (HDL), the only lipoprotein class that can cross the blood brain barrier bidirectionally, is positively associated with cognitive functions. To delineate HDL’s role in Alzhenimer’s disease (AD), we analyzed the chemical properties of plasma HDL from AD and healthy normal adult (control) subjects.Methods and results: By using anion-exchange chromatography, we divided HDL into 5 increasingly electronegative subfractions, H1-H5. Compared to the control cohort (4.24±3.22%; n=20), HDL from AD patients (23.48±17.83%; n=30) had a 5.5-fold increase of H5 (P<0.001; Figure), accompanied by a decreased protein/lipid ratio attributed to a significant reduction of albumin essential for prevention of amyloid beta (Aβ) aggregation. As determined by LC/MSE and ProteinLynx Global SERVER (PLGS), AD-HDL was had a rich content of apolipoprotein (apo)CIII, but diminished amounts of sphingosine-1-phosphate (S1P)-associated apoM and antioxidative paraoxonase 1 (PON1). Exposure of murine RAW 264.7 macrophages to H5 induced vibrant expression of ganglioside GM1 in colocalization with apoCIII on lipid rafts, alongside a concomitant increase of TNF-α detectable in the cultured medium (Figure). LC/MSE examination localized posttranslational oxidation exclusively in ApoA1 residues of H5 in AD-HDL, which exhibited a compromised cholesterol efflux capacity.Conclusions: Plasma HDL from AD patients has a high proportion of H5, an apoCIII-rich electronegative HDL subfraction. The associated reduction in functional (albumin, S1P, apoM) and increase in proinflammatory (apoCIII, PON1, TNF-α) components may favor Aβ assembly and neuroinflammation. Additionally, a compromised cholesterol-efflux capacity of AD-HDL may also contribute to vascular cognitive impairment.