From: ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
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 | |
AD | • APOE2 is associated with genes involved in protein synthesis, folding and degradation, response to unfolded protein, autophagy, and mitochondrial function [139] | Brain | |
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, 297,298,299] | Brain | https://doi.org/10.1038/s41467-020-19737-2 https://doi.org/10.1038/s41586-019-1195-2 |
Normal APOE mice | • APOE4 reduces energy expenditure in young females and decreases glucose oxidation by redirecting flux through aerobic glycolysis [300] | Brain Plasma | |
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 | https://doi.org/10.1016/j.neuron.2020.02.034 https://doi.org/10.1016/j.cell.2017.05.018 |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
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 | |
AD | • APOE4 is associated with reduced levels of CAR, LPC, LPE, PA, PC, PE, PI, PS, SM, and ST [139] | Brain | |
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 | |
Metabolomics | |||
AD | • APOE4 is associated with reduced LysoPC(18:1), LysoPC(P-18:0), and Cardiolipin [308] | Plasma | |
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 | |
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 | |
Normal; Aging | • APOE2 reduces total cholesterol, LDL, lipoprotein A, and ApoB and increases apoA1 compared to APOE3 [311] | blood | |
Normal | • APOE4 is associated with increased SNAP-25 in cognitively normal patients [312] | CSF | |
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 | |
AD | • APOE4 carriers with preclinical AD have increased VILIP-1 [314] | CSF | |
AD | • APOE4 is associated with increased levels of CDH6 and HAGH in AD patients [315] | Plasma | |
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 | |
APOE mice | • APOE4 is associated with increased NP1 levels [317] | Plasma |