Are You ApoE4? 88+ Ways To Increase Apolipoprotein E (ApoE)

Apolipoprotein E (ApoE): Regulator of Fat Metabolism

 
 https://www.ncbi.nlm.nih.gov/pubmed/23384034

https://www.ncbi.nlm.nih.gov/pubmed/23384034

 

Apolipoprotein E (ApoE) is a master regulator for many genes implicated in cholesterol metabolism (such as Alzheimer's Disease and Atherosclerosis).

In this post, we will discuss the benefits and downsides of ApoE, how to determine if you are ApoE2, E3, or E4, and ways to fix it.

Contents:

  1. Basics
  2. Implications Of Normal Or Higher ApoE Activity
  3. Implications Of Lower ApoE Activity
  4. Are You ApoE4? Getting Into Genetics
  5. How To Increase ApoE And ApoE4 Fixes
  6. What Decreases ApoE?
  7. No Effect On ApoE
  8. Mechanism Of Action
  9. More Research

Basics Of ApoE

Apolipoprotein E (ApoE) is a key apolipoprotein that regulates lipid metabolism in the whole body and the brain.

This gene is notoriously known for its correlation to Late Onset Alzheimer's Disease (LOAD) and heart disease. 

Like the name implies ApoE is protein that exerts anti-inflammatory effects on the body immune system cardiovascular system in brain.

Loss of binding of this protein to certain receptors (e.g. ApoE4) has shown to be implicated in various diseases.

In the body, ApoE: R

  • Circulates in the blood as a component of VLDL, chylomicrons and a subclass of HDL - having antioxidant, anti-inflammatory and anti-atherogenic properties
  • Modulates cholesterol metabolism
  • Modulates liver function

In the brain, ApoE: R

  • Regulates axonal growth - ApoE can can be synthesized by neurons, usually in response to insult or injury, to promote integrity and neuronal repair.
  • Regulates delivery of cholesterol to neurons (via ApoE receptors, members of LDL receptor gene family)
  • Regulates synaptic formation
  • Regulates synaptic remodeling 

In the cerebrospinal fluid (CSF) and CNS, ApoE: R

  • Circulates as small particles or disks that resemble the peripheral HDL component. 

In the immune system, ApoE: R

  • Maintains Th1/Th2 balance
  • Modulates machophages

Implications Of Normal Or Higher ApoE Activity

Benefits of high ApoE levels (e.g. ApoE2/ApoE3):

  1. Antibacterial Effects - ApoE can act as an antibacterial - can kill Gram-positive (Staphylococcus aureusBacillus subtilis) and Gram-negative (Pseudomonas aeruginosaEscherichia coliKlebsiella pneumoniae) bacteria R R
  2. Antiparasitic Effects - ApoE can modulate parasites (e.g. Plasmodium spp) R
  3. Antiviral Effects - ApoE can modulate Herpes Simplex Virus-1 (HSV-1), Hepatitis C virus (HCV), and HIV R R
  4. Bigger Brain - ApoE2 is associated with greater cortical thickness R
  5. Clearance of Amyloid-beta - as seen in ApoE3 individuals R
  6. Cholesterol Efflux R
  7. Decreased Risk Of Depression R
  8. Higher ATP levels in brain R
  9. Neuroprotection Against Cognitive Decline - ApoE2 has lower associations to Alzheimer's Disease R R
  10. Longevity - ApoE2 is associated with increased longevity R
  11. Protection Against Tau Tangles  R
  12. Stimulation of Neurite Growth (such as BDNFR

Downsides of high ApoE levels (e.g. ApoE2):

  1. Diabetic Nephropathy - ε2 polymorphism tends to be associated with an increased risk for diabetic nephropathy R
  2. Parkinson's Disease R

Implications Of Lower ApoE Activity

 
 https://www.ncbi.nlm.nih.gov/pubmed/28731260

https://www.ncbi.nlm.nih.gov/pubmed/28731260

 

Benefits Of Lower ApoE (e.g. ApoE4):

  1. Fatigue - Decreased risk of snoring and sleep apnea R 
  2. Vision - Decreased risk of Age-related Macular Degeneration R

Downsides Of Lower ApoE (e.g. ApoE4):

  1. Amyloid-beta Plaque Formation - ApoE4 may favor the deposition and production of Aβ and impair the clearance of Aβ - R
  2. Breaks In The Neuronal Cytoskeleton R
  3. Cancer R
  4. Depression - ApoE4 negatively impacts BDNF-5-HT2A signaling in the female brain R
  5. Disrupted Transport Of Nutrients R
  6. Hemorrhages R
  7. Higher Cholesterol Levels R
  8. Higher Fatigue after Brain Injury R
  9. Higher Homocysteine R
  10. Higher Oxidation Levels R
  11. Higher TMAO R R
  12. Increased Blood–Brain Barrier Leakiness R
  13. Increased Neurodegeneration During Aging R
  14. Increased Toxic Burden - PON1 may be lower in those that are ApoE4, compared to ApoE3 R R
  15. Lower BDNF R
  16. Lower Antioxidant Gene Expression - such as NRF2 and AREs: GST, HO-1NQO1 R
  17. Metabolic Syndrome R
  18. Migraines R
  19. Mitochondrial Dysfunction - Altered membrane potential and decreased level/activity of mitochondrial respiratory enzymes R
  20. Neurite Growth Inhibition R
  21. Neuroinflammation - such as LPS induction on TLR4 R R
  22. Neuronal Death R
  23. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) R R
  24. Proteopathy -more towards cognitive impairment R
  25. Reduced Cerebral Blood Flow R
  26. Tau Tangles - ApoE4 may increase tau hyperphosphorylation, facilitating the formation of neurofibrillary tangles R
  27. Weight Gain - APOE3 is associated with the potential to more efficiently harvest dietary energy and to deposit fat in adipose tissue, while APOE4 carriers tend to increase fatty acid mobilization and utilization as fuel substrates especially under high-fat intake R
  28. Worse Outcome From Mercury Poisoning - ApoE4 seems to potentiate the damage caused by mercury R

Are You ApoE4? Getting Into Genetics

Simply put, although lower levels of ApoE has some benefits, it is probably better to have higher levels of ApoE, thus ApoE2 > ApoE3 > ApoE4.

A very small percentage (rare) of the population may have a copy of E5, E6, or E7. R R R R

Women tend to have a higher change of being ApoE4, but studies have shown to be conflicting and inconclusive. R R

ApoE

rs7412 (I'm CC)

  • T + rs429358 T alleles = ApoE2
    • Less risk for late-onset Alzheimer's
    • Approximately 7% of the population has this allele R
    • Associated with increased and decreased risk of vascular disease, as they may clear dietary fat slowly R R
    • Associated with increased risk of Parkinson's Disease R
  • T + rs429358 C alleles = ApoE3
    • 3x risk for late-onset Alzheimer's R
    • This is the "neutral" genotype, which has an allele frequency of approximately 79 percent. R
  • C + rs429358 C alleles = ApoE4
    • 12x risk for late-onset Alzheimer's R
    • Decreased risk of Age-related Macular Degeneration R
    • Decreased risk of snoring and sleep apnea R 

rs429358 (I'm CT) 

  • T + rs7412 T alleles = ApoE2
    • Less risk for late-onset Alzheimer's
    • Approximately 7% of the population has this allele R
    • Associated with increased and decreased risk of vascular disease, as they may clear dietary fat slowly R R
    • Associated with increased risk of Parkinson's Disease R
  • T + rs7412 C alleles = ApoE3
    • 3x risk for late-onset Alzheimer's R
    • This is the "neutral" genotype, which has an allele frequency of approximately 79 percent. R
  • C + rs7412 C alleles = ApoE4
    • 12x risk for late-onset Alzheimer's R
    • Decreased risk of Age-related Macular Degeneration R
    • Decreased risk of snoring and sleep apnea R  

rs1065853

  • G risk allele for LDL R 

rs405509

  • AA alleles - Risk allele for Alzheimer's - Significant associations with AD independent from sex, age and APOE/epsilon 4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). R

rs438811

  • T risk allele R

rs439401 (I'm TC)

  • T risk allele - associated with HDLC-TG (P = 1.0E-08), R

rs440446 (I'm CG)

  • C Allele - Increased risk of gallstone disease (1.7x), gallbladder cancer (1.8x), and bile duct cancer (3.7x). R
  • C Allele - Increased risk of intestinal cancer. R

rs445925 (I'm GG)

  • Cardiovascular Disease Risk Factors with LDL-cholesterol (P = 8.7×10−19) were strongly significant R
  • Associated with LDL-C response to atorvastatin treatment - the % change in LDL-c with statin therapy at one month was approximately -51% in those with at least one “A” allele at rs445925 compared with -45% in common GG homozygotes R

rs449647 (I'm AA)

  • AA Alleles - Each A Allele means lower ApoE levels and higher association with Alzheimer's Disease R
  • AT Alleles - Possibly lower levels of ApoE R
  • TT Alleles - Normal levels of ApoE R

rs769449

  • A allele - associated with decreased longevity R
  • A allele - associated with cognitive decline among African-Americans (p = 0.005) R
  • Strongly associated with LDL-C (P=4.7×10−7) R
  • Showed a significant association with CSF tau and ptau in both strata, although the effect size was almost two fold higher in individuals with high Aβ42 levels (n=416; Beta: 0.072; P=6.58×10−5, for CSF tau levels) than in individuals with low Aβ42 levels (n=478; Beta: 0.035; P=1.83×10−2, for CSF tau levels) R

rs769452

rs769455 (I'm CC)

  • Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes. R
  • Association of ApoE genetic variants with obstructive sleep apnea in children. R

How To Increase ApoE And ApoE4 Fixes

Top 5 ApoE4 Fixes:

  1. Butyrate
  2. Curcumin
  3. Fish Oil
  4. Ketogenic Diet or Mediterranean Diet with high levels of Olive Oil
  5. Intermittent Fasting

Lifestyle/Diet:

  • Apples R
  • Brain Training/Mental Exercises R
  • Caloric Restriction or Intermittent Fasting - induces neuroprotection via Fgf21/AMPK/mTOR R R
  • Cocoa - improves hyperlipidemia and atherosclerosis, as well as endoplasmic reticulum stress R
  • Education R
  • Exercise R R
  • High Fat Diet - increases plasma and hippocampal mRNA levels of ApoE R
  • Hydrogen Sulfide (H2S) Therapy - inhibits plaque progression R
  • Ketogenic Diet - high fat diet has a greater effect on increasing ApoE in plasma in those that are E4 vs E3 R
  • Low Nitrate Diet - improves endothelial dysfunction and plaque stability R
  • MCTs R
  • Mediterranean Diet - high fat diet has a greater effect on increasing ApoE in plasma in those that are E4 vs E3 R
  • Omega 3's and Fish (PUFAs) R 
  • Oleic Acid (Oils such as Pecan, Canola, Peanut, MacadamiaSunflower, Sesame, Grape Seed, and Olive Oil) R R R
  • Rice Bran - reduced plaque development and liver steatosis R
  • Soy R
  • Spirulina (blue-green algae) R R
  • Tomatoes R

Supplements:

Hormones:

Probiotics:

Drugs:

  • AC-262536 - was able to restore some cognitive abilities by action on the hippocampus. R
  • Aspirin - fish oil may be stronger R
  • Irbesartan - can attenuate atherosclerosis R
  • Simvastatin - attenuates of atherosclerotic lesions R
  • Sitagliptin - Protects against Dyslipidemia-Related Kidney Injury R

Pathways:

  • ABC1 R
  • ApoA-I R
  • ApoA-II R
  • ApoA-IV R
  • AP-1 R
  • AP-2 R
  • CAMP R
  • DPP4 inhibition R
  • EGF - ameliorated cognitive decline and cerebrovascular deficits in female mice that express APOE4 R
  • ER-beta R
  • FGF-1 R
  • HDL R
  • LDL R
  • LXR R
  • NF-kB R
  • NR2C2 R
  • PKA R
  • PPAR-gamma R
  • RXR R
  • SIRT1 R
  • SP1 R
  • TGF-b1 R

Other:

  • Amyloid Beta R
  • GIND25 R
  • Heparinase R
  • HIV R
  • Humanin - HN was able to protect against the development of kidney disease R
  • Neu5Ac - has triglyceride lowering, anti-oxidation, and RCT promoting activities R
  • Sphingomyelin R
  • TEMPOL - increased plaque collagen content, decreased lipid content and increased macrophage numbers R

What Decreases ApoE?

Lifestyle/Diet:

  • Airplane Flights (Short Term Hypoxia) R R 
  • Chicken Extract R
  • EMFs R
  • Heavy Metals (eg Mercury) R
  • Saturated Fat - increases risk of CVD R
  • Vitamin B6 Deficiency R
  • Vitamin C Deficiency R
  • Vitamin E Deficiency R

Other:

  • CSNK2A1 R
  • ERK R
  • JNK R
  • MAPK R
  • p38 R
  • Tpl2 R

No Effect On ApoE

  • Cholesterol (e.g. Eggs) R
  • Smoking - A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease R

Mechanism Of Action

 
 https://lipidworld.biomedcentral.com/articles/10.1186/s12944-016-0288-2

https://lipidworld.biomedcentral.com/articles/10.1186/s12944-016-0288-2

 

Simple:

  • Increases BDNF R
  • Increases Dab1 R
  • Increases HDL R
  • Increases HSPG R
  • Increases IL-10 R
  • Increases MCP-1 R
  • Increases MMP2 R
  • Increases MMP9 (unable to degrade the matrix component elastin) R R
  • Increases NO R
  • Increases PI3K/Akt R
  • Increases Plasmin R
  • Increases PON1 R
  • Increases SIRT1 R
  • Increases TNFa R
  • Reduces Amyloid beta - apoE competes with Aβ for cellular uptake through apoE receptors R R
  • Reduces APP R
  • Reduces Caveolin-1 R
  • Reduces Total Cholesterol R
  • Reduces COX2 R
  • Reduces ECE-1 R
  • Reduces eNO R
  • Reduces eNOS R
  • Reduces IL-1b R
  • Reduces IL-2 R
  • Reduces IL-6 R
  • Reduces IL-18 R
  • Reduces LOX-1 R
  • Reduces NAG R
  • Reduces NF-kb R
  • Reduces NMDA R
  • Reduces PAI-1 R
  • Reduces PTLP R
  • Reduces p65 R
  • Reduces TGF-b1 R
  • Reduces Triglyceride R
  • Reduces TIMP1 R
  • Reduces TLR3 R
  • Reduces TLR4 R
  • Reduces VCAM-1 R

Advanced:

  • Through its interaction with the LDL-receptor family members, apoE participates in the cholesterol transport. R
  • In plasma, apoE mediates the clearance of lipoprotein remnants, while in the vascular wall apoE secreted by the macrophages participates in the cellular cholesterol efflux from the atheroma. R
  • Macrophage-specific expression of apoE is atheroprotective even if it has no effect on the plasma lipid levels. R
  • Under inflammatory stress, macrophage-derived apoE is decreased and hence its local beneficial effect is diminished (abolished). R
  • In the brain, the astrocytes represent the main supplier of apoE, the most abundant apolipoprotein in the cerebrospinal fluid. R
  • ApoE4 binds to the promoter of SIRT1 itself and shuts down SIRT1 by 80%. R
  • When you are in an ApoE4/RelA dominant state - it creates an inflammatory response that involves RelA (then they switch into defensive mode).
  • If you are in an ApoE3/SirT1 dominant state (sirt1 is activated by resveratrol etc) - you are in the opposite state of the apoe4 state and you put your energy into metabolism/longevity, etc.
  • ApoE4 goes into the nucleus and interacts with RelA (part of NF-kB, which is part of the inflammatory response). when it goes into the nucleus, it binds with 1700 different gene promotors (changes the programming of the cell).
  • An important pathway of Aβ clearance is via the low-density lipoprotein receptor-related protein-1 (LRP1), located at the blood-brain barrier (BBB). R
  • Exogenous apoE inhibits macrophage inflammatory responses to TLR-4 and TLR-3 agonists through distinct mechanisms related to receptor and HSPG binding respectively. R
  • ApoE exerts anti-inflammatory effects, switching macrophage phenotype from the proinflammatory M1 to the anti-inflammatory M2, suppressing CD4+ and CD8+ lymphocytes, and reducing IL-2 production. R 
  • The anti-oxidative properties of apoE are isoform-dependent, modulating the levels of various molecules (Nrf2 target genes, metallothioneins, paraoxonase). R

More Research

  • APOE ε7 could serve as another risk factor for cognitive impairment and is particularly associated with vascular disease. R
  • APOE E2/E2 might be one of the factors affecting warfarin dose requirements. R