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Hussein Yassine, M.D.: Deep Dive Into The “Alzheimer’s Gene” (APOE), Brain Health, And Omega-3s | The Drive With Peter Attia #147

Key Takeaways

  • The brain is an electrical system that uses lipids to facilitate firing but uses glucose for energy
  • The brain prefers glucose as the predominant source of energy via GLUT1; the rest of the body uses GLUT4 (insulin-regulated transporter)
  • The brain does its best to regulate glucose content, not dependent on insulin signaling
  • When glucose is not available, the brain extracts all ketone bodies from fatty acids outside the brain to maintain itself  
  • Historically, ApoE4 was associated with better outcomes prenatally and against parasite and disease – that changed as more movement, interbreeding, and dietary challenges took place
  • “If you have two copies of ApoE4, your chance of getting Alzheimer’s disease increases 12-fold. If you have one copy of ApoE4 your chance of getting Alzheimer’s increase 2-4 fold” – Dr. Hussein Yassine
  • Unlike ApoA or ApoB you can’t make an assumption about the function of ApoE based on its concentration
  • Ancestral diets rich with meat supported richness of ApoE4 – moving to a plant-based diet, increase in carbs supported ApoE 2 and ApoE 3 because they support GLUT1 expression
  • We rely on diet to get omega-3s: the human body doesn’t have an efficient system to make EPA and DHA
  • “Omega-3 fatty acids are important for the brain, we can’t make them efficiently, and we’re not consuming enough of them.” – Dr. Hussein Yassine
  • There isn’t enough evidence to suggest supplementing with omega-3s but there is enough to suggest eating one serving of fatty fish per week

Introduction

Hussein Yassine, M.D. is an Associate Professor in the Department of Medicine at the University of Southern California (USC), specializing in lipid metabolism and cognition and the risk these both have on developing cognitive impairment. Dr. Yassine’s lab focuses on lipid metabolism and nutrition as risk factors for Alzheimer’s disease. Specifically, Dr. Yassine’s research studies the ApoE4 allele, currently the strongest genetic risk factor for developing Alzheimer’s disease.

In this episode of The Drive, Dr. Hussein Yassine and Peter Attia take a deep dive into ApoE4 and its implications in Alzheimer’s disease and the utilization as the brain’s fuel. They also discuss research hot topics like EPA, DHA, and omega-3s.

Host: Peter Attia (@PeterAttiaMD)

Biology & Physiology Of The Brain

  • The brain grows rapidly between ages 3-5 and is almost fully developed by age 6
  • The brain is a lipid organ, carrying weight from fatty acids, cholesterol
  • The brain requires an abundance of lipid and cholesterol to function optimally
  • The brain operates by firing – it’s an electric system, using lipids to facilitate for optimization
  • The main cells of the brain are neurons, helper cells, and microglial cells
  • Neurons fire and form synapses, regulating how the cells function
  • Helper cells work with neurons to regulate energy and storage production required for neurons to fire
  • Microglial cells are immune cells responsible for cleaning up – and have been linked to neurodegenerative disease
  • The brain is surrounded by blood-brain barrier, protecting it from the outside so its environment is stabilized
  • Blood-brain barrier prevents toxins from entering the brain
  • Cerebrospinal fluid (CSF) is the “sewage system” of the brain, delivering nutrients and allowing drainage of excess fluid
  • Constant CSF activity and drainage is critical for maintaining a healthy brain

Energy In The Brain Versus The Rest Of The Body

  • The brain accounts for about 2% of our body weight but uses about 20% of our energy
  • The brain prefers glucose as the predominant source of energy – the rest of the body uses GLUT4 (insulin-regulated transporter)
  • GLUT4 can be induced by exercise, changes in body weight
  • At the blood-brain barrier, only GLUT4 plays a minor role – GLUT1 is predominant
  • GLUT1 expression is not controlled by diet, exercise, or typical insulin-regulated mechanisms
  • The function of GLUT1 in the blood-brain barrier is to protect the brain and maintain a relatively constant amount of glucose
  • In Alzheimer’s disease and other disease states: there’s leakage of the blood-brain barrier and GLUT1 so the brain struggles to capture glucose from the system
  • The brain is not efficient in utilizing fat as ATP (body’s energy)
  • The brain is a fatty organ but does not store fat, it uses fat to regulate membrane fluidity
  • The preferred food of neurons is lactate
  • Glucose gets into the astrocyte where it is shuttled and changed to lactate
  • In fasting and glycogen depletion: the brain becomes efficient at extracting ketones to maintain firing and prevent a coma-like state
  • Energy in the brain: (1) brain does its best to regulate glucose content, not dependent on insulin signaling; (2) brain prefers glucose versus fat as a source of energy; (3) when glucose is not available, the brain extracts all ketone bodies from fatty acids outside the brain to maintain itself  

Apolipoprotein (APoE) In The Blood

  • ApoE is a protein that exists in different isoforms
  • Orchestra/conductor analogy: ApoB would be a principal player; ApoA would be a star player who can lead sometimes (e.g., piano, violin); ApoE and ApoC3 are the conductors that regulate the speed and rhythm at which things are happening
  • ApoE can change based on lipid binding and moves regularly
  • A fundamental aspect of metabolic syndrome is ApoE and ApoC3 are not mobile
  • We can measure ApoA and ApoB in circulation but there’s no assay to measure ApoE in circulation
  • Unlike ApoA or ApoB you can’t make an assumption about the function of ApoE based on its concentration

APoE In The Brain

  • ApoE in the brain isn’t facilitating clearance of lipids – its role is multi-functional, supporting astrocytes (which support neurons)
  • ApoE in a glial cell: regulate inflammation of the glial cell
  • ApoE in astrocyte: remove cholesterol from astrocyte and give it to neuron
  • ApoE will be released at high rates to make sure repair happens in the disorder
  • ApoE largely escapes degradation – it can get in and out of the cell, fine-tuning inflammatory pathway tied to lipid pathway

Evolution Of Apolipoprotein

  • ApoE is capable of turning a cell into an acute inflammatory state
  • ApoE is like a thermostat structural flexibility: when the cell expresses ApoE it changes its lipid content and will become more or less likely to be inflamed depending on the state
  • ApoE4 has a large propensity to aggregate
  • Aggregation of ApoE4 in microglial and make an acute inflammatory response more efficient
  • Historically, ApoE4 was associated with better outcomes – that changed as more movement, interbreeding, and dietary challenges took place
  • Historically: women who developed ApoE4 were better equipped to fight a septic environment, had better birth outcomes, less parasitic infection
  • Historically: ApoE4 carriers live/lived better, without Alzheimer’s – even if these carriers died earlier from other causes
  • ApoE4 thrives on dietary lipid environment
  • Historically: ApoE4 carriers used to consume diets higher in protein and fat, lower carb
  • Now, carrying one or two copies of ApoE4 increases the risk of developing Alzheimer’s disease
  • Theory: mass movement of our ancestors was associated with significant changes in diet that could have put pressure on ApoE4 and allowed ApoE2 and ApoE3 to thrive
  • Ancestral diets rich with meat supported richness of ApoE4 – moving to a plant-based diet, increase in carbs supported ApoE 2 and ApoE 3 because they support GLUT1 expression

Not All ApoE4 Carriers Have The Risk Of Alzheimer’s Disease

  • “If you have two copies of ApoE4, your chance of getting Alzheimer’s disease increases 12-fold. If you have one copy of ApoE4 your chance of getting Alzheimer’s increase 2-4 fold” – Dr. Hussein Yassine
  • ApoE2/ ApoE4 carriers can go either way because ApoE2 is protective
  • People who live in Nigeria have substantially less risk of getting Alzheimer’s disease versus those in the U.S. and Japan
  • LatinX population carrying ApoE4 do not have the same risk of developing Alzheimer’s disease as those in U.S. and Japan
  • ApoE4 is found on chromosome 19 with gene variants getting coinherited with ApoE4
  • As generations are crossed and interbred, the fidelity of linkages are lost 
  • Its possible ApoE4 is not enough but to increase the risk of disease but has to be in an environment that promotes pathogenicity  
  • ApoE4 carriers with diabetes are at higher risk than ApoE4 carriers without diabetes
  • ApoE4 is still a disease of aging – young carriers don’t develop Alzheimer’s symptoms earlier
  • New study: in the older ApoE4 brain in dementia, upregulates enzymes that regulate its digestion to extract fatty acids and produce ATP
  • Recommendation for younger ApoE4 carriers may be different than young carriers

Diet Interactions Of ApoE4

  • ApoE4 makes GLUT1 less successful at the blood-brain barrier
  • GLUT1 is regulated by peripheral glucose concentration
  • An environment rich in glucose (insulin-resistant): ApoE4 carriers are more susceptible to disease
  • Type 2 diabetes is too broad a spectrum to say that sufferers are at a higher risk for Alzheimer’s via ApoE4 – in part because type 2 diabetes is such a wide spectrum
  • ApoE4 could be a factor in why an individual gets type 2 diabetes in the first place
  • Diet interaction with ApoE4 is contingent on aging and a second or third hit (e.g., inflammation, energy starvation, etc.)
  • Ketosis for brain health in ApoE4 carriers is less beneficial than non-carriers

Omega-3 Fatty Acids, EPA, DHA

  • The brain is highly enriched in omega-3 and omega-6
  • Fatty acids facilitate neuronal firing and efficiency
  • DHA: building block; most commonly found omega-3 in the brain
  • EPA: less abundant in the brain but potent anti-inflammatory properties
  • We rely on diet to get omega-3s: the human body doesn’t have an efficient system to make EPA and DHA
  • It’s likely a lack of omega-3s contributes to disease and puts individuals at higher risk
  • Supplementation with omega-3s comes from marine life because the complexity of structure requires something found in algae
  • DHA deficiency is detrimental to the function of the brain
  • The brain in younger ApoE4 carriers take up as much DHA as possible to maintain function
  • In infancy, deficient polyunsaturated fatty acids are associated with poorer outcomes in school
  • The brain is almost fully grown by age 6 and begins to atrophy around age 60
  • The role of omega-3 in the diet between 6 and 60 is uncertain
  • There may be an age range in which it’s crucial to consume high amounts of DHA before it’s futile
  • The half-life of lipids in the brain is substantially longer than in other locations
  • We don’t have the evidence to support omega-3 supplementation but there is enough evidence to suggest one serving of fatty fish per week

Lifestyle for ApoE4 Carriers

  • If your parents knew at birth and have ethnicity, risk factors, etc:
    • Consume adequate omega-3 from fatty fish, not supplement
    • Make sure blood pressure is controlled
    • Exercise throughout life to reduce cardiovascular risk
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