Table 1.
ApoE-targeted strategies for treatment of Alzheimer disease
| Strategy | Rationale | Examples |
|---|---|---|
| Pharmacological approaches | ||
| Modulate ApoE levels | Promotes Aβ clearance, lipid homeostasis and synaptic function | LXR/RXR agonists, small molecules |
| Increase ABCA1 expression | Promotes ApoE lipidation and stabilizes ApoE, thereby decreasing amyloid deposition | LXR/RXR agonists, small molecules |
| Disrupt ApoE–Aβ interaction | Reduces Aβ aggregation and deposition | Aβ12–28P, small molecule inhibitors, ApoE-specific antibody |
| Conversion of ApoE4 to ApoE3 | Increases ApoE3-associated protective functions and decreases ApoE4-related toxic effects | Small compounds (i.e., disulphonate and (monosulphoalkyl) |
| Restore ApoE functions | Increases ApoE protective functions and decreases neuroinflammation | ApoE-mimetic peptide |
| Blockade of ApoE fragmentation | Decreases tau pathology, and toxicity to mitochondria | Inhibitors for specific proteinases involved in ApoE fragmentation |
| Increase LRP1 and/or LDLR levels | Enhances Aβ clearance, cholesterol transport and synaptic plasticity | Small molecules |
| Increase apoE receptor 2 and/or VLDLR levels | Increases ApoE signalling and synaptic plasticity | Small molecules |
| Restore brain vascular integrity | Eliminates ApoE4-mediated blood–brain barrier breakdown and leakage of blood-derived toxic molecules | Cyclosporine A |
| Nonpharmacological approaches | ||
| APOE genotyping prior to immunotherapy | Helps to predict clinical outcome for Aβ-targeted or other therapies | Aβ immunotherapy might be more effective in APOE ε4 carriers or noncarriers |
| Preventive care | Maintains healthy brain vasculature function | Physical exercise, intellectual activities (e.g., puzzles), social connections (e.g., calling family and friends), healthy diet |
Abbreviations: Aβ, amyloid-β; ABCA1, ATP-binding cassette transporter A1; AD, Alzheimer disease; ApoE, apolipoprotein E; LDLR, low-density lipoprotein receptor; LRP1, low-density lipoprotein receptor-related protein 1; LXR, liver X receptor; RXR, retinoid X receptor; VLDLR, very-low-density lipoprotein receptor.