Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease

Abstract

Isoforms of Apolipoprotein E (ApoE) determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between ApoE and Amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that in the early stages of aggregation, all isoforms of ApoE associate with Aβ in large co-aggregates, but then fall away as fibrillation happens. Similar large co-aggregates exist in the brains of AD patients, accounting for around 50% of the mass of aggregated Aβ detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. The cellular uptake and toxicity of these large co-aggregates are isoform-dependent, suggesting a mechanistic role for ApoE-Aβ interactions in AD.