Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer’s Disease

Abstract

The APOE ɛ4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ɛ3 conventionally is considered as ‘risk neutral’ although APOE ɛ3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOE ɛ3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOE ɛ4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients). Total plasma apoE levels were lower in APOE ɛ4-carriers and overall correlated significantly to CSF Aβ₄₂, p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ɛ3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE ɛ3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ɛ3 subjects.