Plasma ApoE4 Levels Are Lower than ApoE2 and ApoE3 Levels, and Not Associated with Plasma Aβ_40/42 Ratio as a Biomarker of Amyloid-β Amyloidosis in Alzheimer’s Disease

Article type: Research Article

Authors: Nakamura, Takumi^{a; e; *} | Kawarabayashi, Takeshi^{a; b; e} | Ueda, Tetsuya^c | Shimomura, Sachiko^c | Hoshino, Masaki^c | Itoh, Ken^d | Ihara, Kazushige^e | Nakaji, Shigeyuki^e | Takatama, Masamitsu^b | Ikeda, Yoshio^a | Shoji, Mikio^{a; b; e}

Affiliations: [a] Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan | [b] Department of Neurology, Geriatrics Research Institute and Hospital, Maebashi, Japan | [c] Bioanalysis Department, LSI Medience Corporation, Itabashi-ku, Tokyo, Japan | [d] Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan | [e] Department of Social Medicine, Hirosaki University School of Medicine, Hirosaki, Japan

Correspondence: [*] Correspondence to: Takumi Nakamura, MD, PhD, Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan. Tel.: +81 272 20 8292; Fax: +81 272 20 8068; E-mail: [email protected].

Abstract: Background:APOE4 is the strongest risk factor for Alzheimer’s disease (AD). However, limited information is currently available on APOE4 and the pathological role of plasma apolipoprotein E (ApoE) 4 remains unclear. Objective:The aims of the present study were to measure plasma levels of total ApoE (tE), ApoE2, ApoE3, and ApoE4 using mass spectrometry and elucidate the relationships between plasma ApoE and blood test items. Methods:We herein examined plasma levels of tE, ApoE2, ApoE3, and ApoE4 in 498 subjects using liquid chromatograph-mass spectrometry (LC-MS/MS). Results:Among 498 subjects, mean age was 60 years and 309 were female. tE levels were distributed as ApoE2/E3 = ApoE2/E4 >ApoE3/E3 = ApoE3/E4 >ApoE4/E4. In the heterozygous group, ApoE isoform levels were distributed as ApoE2 >ApoE3 >ApoE4. ApoE levels were not associated with aging, the plasma amyloid-β (Aβ) 40/42 ratio, or the clinical diagnosis of AD. Total cholesterol levels correlated with the level of each ApoE isoform. ApoE2 levels were associated with renal function, ApoE3 levels with low-density lipoprotein cholesterol and liver function, and ApoE4 levels with triglycerides, high-density lipoprotein cholesterol, body weight, erythropoiesis, and insulin metabolism. Conclusion:The present results suggest the potential of LC-MS/MS for the phenotyping and quantitation of plasma ApoE. Plasma ApoE levels are regulated in the order of ApoE2 >ApoE3 >ApoE4 and are associated with lipids and multiple metabolic pathways, but not directly with aging or AD biomarkers. The present results provide insights into the multiple pathways by which peripheral ApoE4 influences the progression of AD and atherosclerosis.

Keywords: Alzheimer’s disease, amyloid-β , ApoE, biomarkers, cholesterol, HDL, isoform, LDL

DOI: 10.3233/JAD-220996

Journal: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 333-348, 2023