Table 1.
APOE isoform effects in aging and AD: Insights from multi-omics and biomarker studies
| Cohort | Findings | Source | DOI |
|---|---|---|---|
| Transcriptomics | |||
| Normal; AD | • APOE2/3 AD brains are enriched in complement pathway genes (C4A, C4B, and HSPA2) whose expressions are associated with an increase of pTau231/tTau [296] | Brain | 10.1038/s41380-021-01266-z |
| AD | • APOE2 is associated with genes involved in protein synthesis, folding and degradation, response to unfolded protein, autophagy, and mitochondrial function [139] | Brain | 10.1186/s13195-019-0558-0 |
| Normal; AD | • APOE is one of the DAM-like signature genes that is significantly up-regulated in human AD brain assessed by single cell- or single nuclei-RNA Sequencing [64, 297–299] | Brain |
10.1038/s41467-020-19737-2 10.1038/s41586-019-1195-2 10.1007/s00401-020-02200-3 10.1007/s00401-021-02263-w |
|
Normal APOE mice |
• APOE4 reduces energy expenditure in young females and decreases glucose oxidation by redirecting flux through aerobic glycolysis [300] |
Brain Plasma |
10.1186/s13024-021-00483-y |
|
APOE mice Amyloid mouse models |
• APOE4 increases the expression of Serpina3 family genes, whereas APOE2 drives distinct blood metabolome profile [173] • DAM/MGnD/ARM exhibit conserved transcriptional signatures across different AD mouse models with Apoe being one of the central regulators [116, 118, 301] |
Brain Plasma |
10.1016/j.neuron.2020.02.034 10.1016/j.cell.2017.05.018 10.1016/j.immuni.2017.08.008 10.1016/j.celrep.2019.03.099 |
| Normal |
• Microglial gene expression modules associated with APOE4 and sex are also enriched with genes involved in cholesterol absorption and lipid digestion [302] • Microglial gene expression modules associated with APOE4 and age suggest perturbations in lipid and carbohydrate metabolism as well as microglial activation [302] |
Brain | 10.1111/acel.13606 |
|
Normal; AD APOE mice |
• APOE4 astrocytes and microglia demonstrate dysregulated lipid metabolism [179] • APOE4 alters the matrisome, ECM, and immune pathways in hiPSC-mixed cortical cultures and AD brains [179] |
Brain hiPSC |
10.1016/j.cell.2022.05.017 |
| Proteomics | |||
| Normal; AD | • AIF1, APP, GDI2, HSP90AA1, METAP2, NACA, NCK1, PRDX1, RPS27A, SFTPD and UFC1 are downregulated in AD versus control among APOE4 carriers. [303] | Plasma, brain | 10.18632/aging.202950 |
| Normal |
• APOE genotype is associated with levels of PSD95 in superior temporal cortex in AD (E4/* > E3/E3 > E2/*) [59] • APOE2 is associated with significantly increased levels of PSD95 in superior temporal cortex [59] |
Brain | 10.1016/j.neurobiolaging.2005.04.008 |
| Control; AsymAD; AD | • The matrisome module (i.e., extracellular matrix associated proteins) is influenced by the APOE4 but is not associated with cognitive decline rate after adjustment for neuropathology [304]. | Brain | 10.1038/s41593-021-00999-y |
| Lipidomics | |||
| Normal; AD |
• APOE4 copy number is positively associated with LysoPE and acylcarnitine species [305] • APOE4 copy number is negatively associated with PE(O), PE(P), ceramides, and triglycerides versus APOE2 carriers [305] |
Plasma | 10.3233/jad-191304 |
| Normal; Aging |
• LDL cholesterol levels are genotype dependent (E4/E4 > E4/E3 > E3/E3 > E2/E3 > E2/E2) [306] • APOE2 is associated with increased levels of most phospholipids (i.e., lysophosphatidylcholines and all PE subclasses) [306] • APOE4 is associated with reduced levels of phosphatidylinositol relative to APOE2 and APOE3 carriers [306] |
Plasma | 10.3233/jad-190524 |
| AD | • APOE4 is associated with reduced levels of CAR, LPC, LPE, PA, PC, PE, PI, PS, SM, and ST [139] | Brain | 10.1186/s13195-019-0558-0 |
| Apoe-KO mice |
• Both APOE3 and APOE4 treatment reduces hyperlipidemia in a dose-dependent manner, lowering both plasma cholesterol and lipoprotein levels [307] • Expression of APOE4 increases VLDL-cholesterol and reduces HDL-cholesterol levels relative to apoE3 [307] |
Plasma | 10.1161/atvbaha.112.301193 |
| Metabolomics | |||
| AD | • APOE4 is associated with reduced LysoPC(18:1), LysoPC(P-18:0), and Cardiolipin [308] | Plasma | 10.1016/j.jpba.2019.113088 |
| Normal; Young |
• APOE4 carriers show higher levels of cholesterol relative to APOE2 carriers [309] • APOE influences GlycA, isoleucine, LDL-TG, VLDL-TG, and M-VLDL (E2 < E3 < E4) [309] • APOE influences LDL particle diameter (E2 > E3 > E4) [309] |
Serum | 10.1038/s41598-018-36450-9 |
| Biomarkers | |||
| Normal |
• APOE4 is associated with increased LDL, IGF-1, SHBG, bilirubin, triphosphate, ApoB, and total cholesterol, and reduced HDL, HbA1C, lipoprotein A, CRP, GGT, vitamin D, creatine, urate, and urea compared to APOE3 [310] • APOE2 is associated with increased HDL, CRP, vitamin D, CysC, ApoA, creatinine, and alkaline phosphatase; and reduced LDL, IGF-1, bilirubin, and ApoB, compared to APOE3 [310] |
Serum blood | 10.3233/jad-200338 |
| Normal; Aging | • APOE2 reduces total cholesterol, LDL, lipoprotein A, and ApoB and increases apoA1 compared to APOE3 [311] | blood | 10.18632/aging.103405 |
| Normal | • APOE4 is associated with increased SNAP-25 in cognitively normal patients [312] | CSF | 10.1016/j.neurobiolaging.2021.02.008 |
| Normal; Aging |
• APOE2 carriers without dementia have reduced Aβ burden, with no differences in tau accumulation [313] • APOE4 carriers without dementia have increased Aβ burden and tau burden [313] |
PET | 10.1007/s00259-021-05192-8 |
| AD | • APOE4 carriers with preclinical AD have increased VILIP-1 [314] | CSF | 10.2147/ndt.s235395 |
| AD | • APOE4 is associated with increased levels of CDH6 and HAGH in AD patients [315] | Plasma | 10.1038/s41598-020-65038-5 |
| AD |
• Levels of CRP are influenced by APOE (E2/E3 > E3/E3 > E3/E4 > E4/E4 > E2/E4) [316] • Levels of ApoB are influenced by APOE (E2/E3 < E2/E4 < E3/E3 < E3/E4 < E4/E4) [316] • Levels of IL-13 are influenced by APOE (E2/E3 < E2/E4 < E3/E3 < E3/E4 < E4/E4) [316] • Levels of CXCL9 are influenced by APOE (E3/E3 > E3/E4 > E4/E4) [316] |
Plasma | 10.1001/archneurol.2012.1070 |
| APOE mice | • APOE4 is associated with increased NP1 levels [317] | Plasma | 10.1016/j.nbd.2018.02.014 |
Abbreviations: pTau: phosphorylated Tau, tTau: total Tau, DAM: disease-associated microglia, MGnD: microglial neurodegenerative phenotype, ARM: activated response microglia, AIF1: Allograft inflammatory factor 1, APP: Amyloid precursor protein, GDI2: Guanosine Diphosphate Dissociation Inhibitor 2, HSP90AA1: Heat Shock Protein 90 Alpha Family Class A Member 1, METAP2: Methionyl Aminopeptidase 2, NACA: Nascent Polypeptide Associated Complex Subunit Alpha, NCK1: Non-catalytic region of tyrosine kinase adaptor protein 1, PRDX1: Peroxiredoxin 1, RPS27A: Ribosomal Protein S27a, SFTPD: Surfactant Protein D, UFC1: Ubiquitin-Fold Modifier Conjugating Enzyme 1, PSD95: Postsynaptic density protein 95, AsymAD: asymptomatic AD, LysoPE: Lysophosphatidylethanolamine, PE: Phosphatidylethanolamine, LDL: Low-density lipoprotein, CAR: Carnitine, LPC: Lysophosphatidylcholine, LPE: Lysophosphatidylethanolamine, PA: Phosphatidic acid, PC: Phosphatidylcholine, PI: Phosphatidylinositol, PS: Phosphatidylserine, SM: Sphingomyelin, ST: Sterol, VLDL: Very low-density lipoprotein, HDL: High-density lipoprotein, LysoPC: Lysophosphatidylcholine, GlycA: Glycoprotein acetylation, TG: Triglyceride, IGF-1: Insulin-like growth factor-1, SHBG: Sex hormone binding globulin, HbA1C: Hemoglobin A1C, CRP: C-reactive protein, GGT: Gamma-glutamyl transferase, CysC: Cystatin C, ApoA: Apolipoprotein A, ApoB: Apolipoprotein B, VILIP-1: Visinin-like protein 1, CDH6: Cadherin 6, HAGH: Hydroxyacylglutathione Hydrolase, IL-13: Interleukin-13, CXCL9: Chemokine ligand 9, NP1: Neuronal pentraxin 1