Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer's disease (AD) compared to APOE2 and APOE3. Amyloid-beta (A beta), particularly in a soluble oligomeric form (oA beta), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oA beta are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oA beta levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with A beta, namely apoE/A beta complex, modulate A beta levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/A beta complexes, resulting in reduced apoE4/A beta levels and increased accumulation, particularly of oA beta. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed.