Fig. 2.

ApoE-targeted therapeutic strategies for AD. One avenue of AD therapy is modulating apoE expression from various cell types. This can be achieved through LXR/RXR agonists which increase apoE levels and lipidation. LXR/RXRs are upstream regulators of apoE expression making them a suitable target for modulating apoE levels. Targeting apoE should also consider the isoform- and cell type-specific effects. Another apoE-targeted therapeutic strategy is the use of small molecules that modulate apoE functions. These include peptides designed to mimic the binding site for apoE on LDL and HDL, which has been shown to increase apoE lipidation and secretion. Additionally, mimetic peptides can increase the function of apoE receptors to improve cholesterol transport. Small molecules or immunotherapies that prevent apoE self-association and/or aggregation may increase the lipid carrying capacity of apoE and reduce Aβ seeding. Similarly, modulating the lipidation of apoE has become an interesting target. Mimetic peptides can be used to increase the activity of ABCA1, which increases the lipidation of apoE4 and improves cognitive function. This can also be achieved through anti-sense oligonucleotide (ASO) inhibition of miR-33. Another promising therapeutic avenue is structural modification of apoE through genetic manipulation or small molecules. The CRISPR/Cas9 system has the potential to directly convert APOE4 to APOE3 or APOE2. This may also be achieved through an AAV system to induce apoE2 expression. A similar approach without genetic manipulation would be small molecule inhibitors to reduce interdomain interactions and structurally modify apoE to alter its function. Lastly, targeting peripheral apoE may be an alternative avenue for AD therapy. For example, plasma exchange by infusing APOE3 young plasma in APOE4 carriers is currently being tested in clinical trials to determine the beneficial effects of young plasma and the isoform-dependent effects. While these various therapeutic approaches have shown some promise in preclinical and clinical settings, they have yet to make a significant impact on the overall prognosis of AD. Research continues to seek alternative approaches to refine the current therapeutic strategies. Presently, many new technologies are being employed to discover new targets and networks such as transcriptomics, proteomics, lipidomics, and metabolomics. These multi-omics and integrative analysis may help better inform future apoE-related disease modifying therapy for AD.