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

Which isoforms of apolipoprotein E (apoE) we inherit 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 all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ∼50% of the mass of soluble Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces inflammation and membrane damage, demonstrating a clear path to AD therapeutics. ### Competing Interest Statement D.M.H. is an inventor on a patent licensed by Washington University to NextCure on anti-apoE antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics, DenaliGenentech, and Cajal Neuroscience. D.M.H. consults for Alector. The lab of D.M.H. receives research grants from the National Institutes of Health, Cure Alzheimer's Fund, Tau Consortium, the JPB Foundation, Good Ventures, the Rainwater Foundation, NextCure, Denali, and Ionis. D.C.C. and P. T. hold stock in AstraZeneca. All the other authors declare no conflicts of interest.