Francisco Gonzalez-Lima, Ph.D.: Advancing Alzheimer’s Disease Treatment and Prevention – The Peter Attia Drive

Check out The Peter Attia Drive Episode Page & Show Notes

Key Takeaways

  • Our knowledge of the brain surpasses any other organ yet there’s a TON that we still don’t know about it
  • “We have not made any significant progress in Alzheimer’s disease research. This is the largest failure of the biomedical research enterprise during my lifetime.”
  • Today, many believe that if we find out what’s happening with Early-Onset Alzheimer’s Disease (EOAD) cases then we can cure the more common senile, older age late-onset dementia – this is NOT true (the pathologies are vastly different)
    • Even though a VERY small percentage of people that are described as having Alzheimer’s disease belong to this early-onset category, this is where over 90% of the research is focused
  • The epidemiology shows that there’s no greater association with Alzheimer’s disease (or cardiovascular disease) than age
  • 3 alternative Alzheimer’s disease treatment methods: Methylene blue, infrared light, and the ketogenic diet
  • The health of the heart is very closely related to the health of the brain
    • Whatever you do that improves cardiovascular health will also improve brain health

Intro

  • Francisco Gonzalez-Lima, is a Professor of Neuroscience and Pharmacology & Toxicology at the University of Austin Texas

Books Mentioned

About Francisco Gonzalez-Lima

  • Francisco has been a tenured professor for 27 years
  • He describes himself as a “behavioral neuroscientist”
    • He became fascinated by the brain while watching his professor dissect one in an undergraduate course
      • Our knowledge of the brain surpasses any other organ yet there is a TON that we still don’t know about it
  • As a Humboldt fellow in Germany, FRancisco was using functional brain mapping to understand how behavioral functions reflected in brain activity
    • This led to the creation of FDG-PET scans (the first functional imaging technique in humans)

The Unique Nature of the Human Brain

  • The brain is specialized to handle large amounts of communication and has lots of “highways” to carry information
    • One cannot simply look at the brain the same way you look at other organs. Because of that circuit property, it allows the developing of computational power. The brain uses the circuits not just for communication, which is the most obvious function, but to determine and compute outcomes that are used to guide the other tissues in the body.”
  • The majority of brain mass in humans is in the cerebral cortex
  • Both the brain stem and spinal cord are responsible for many of the reflexes that take place without us taking conscious action (i.e. breathing)
  • Our anatomy is redundant and parallel
    • We have two arms, two legs, etc.
    • The brain takes this redundancy to the extreme: the redundancy is combined with the acquisition of new networks or circuit options
      • The brain uses this redundancy and “converges” on the right action or strategy
        • In other words, you have all these multiple parallel systems and they’re doing these computations, but only the ones that converge on the same solutions are the those that are acknowledged and move on for the next stage

Humans vs Animal Brain

  • In primates/mammals, the cerebral cortex is the dominant component of the brain
    • With reptiles or amphibians, the midbrain (mesencephalon) is the largest part of the brain/most dominant
  • In mammals, we have to move information to the level of the thalamus (which is a bit higher than the midbrain)
    • We then pass information from the thalamus to the cerebral cortex and which is then fed back down to the output systems
      • The main roles of the cerebral cortex are:
        • To provide us the ability to delay a response
        • To allow us to compute what the consequences are if we were to go through with that response
  • Nearly all of the neurodegenerative diseases are seen in the cerebral cortex (exception being Parkinson’s exists mainly in the midbrain)

The Misunderstanding of Alzheimer’s Disease

  • “We have not made any significant progress in Alzheimer’s disease research. This is the largest failure of the biomedical research enterprise during my lifetime.”
  • The main reason we’ve made so little progress is that “we have remained faithful to an initial observation” in 1907 by Alois Alzheimer looking at a patient who died of early onset dementia
    • What Alzheimer described in the brain of that individual as Alzheimer’s disease is NOT the same disease that is happening in older people today
      • This has been the most basic misunderstanding from the very beginning
  • In 9 out of 10 cases of Alzheimer’s disease, there is absolutely no inheritance or familial component
    • Instead, it develops very slowly over decades

Alzheimer’s Disease Research

  • Alois Alzheimer’s case study of his patient in 1907 was likely a case of what we now refer to as Early-Onset Alzheimer’s Disease (EOAD)
  • EOAD is a hereditary disease
    • Less than 1% of the population is affected by EOAD
      • Even though a very small percentage of people that are described as having Alzheimer’s disease belong to this early-onset category, this is where over 90% of the research is focused
  • Today, many believe that if we find out what’s happening in the early-onset cases then we can cure the more common senile, older age late-onset dementia
    • “And that false premise is what’s been driving all these failures”
      • “There is absolutely no correlation or relationship between the amount of amyloid-beta deposition and the onset of memory deficits, cognitive impairment, or the progression of the disease”

Cognitive Decline

  • Anterograde amnesia is the inability to form short-term memories – this is the first sign of Alzheimer’s Disease (AD)
    • This is caused by a functional deficit that’s interfering with what we call “working memory”
  • Memories have 3 stages:
    • Immediate memory: you can remember something for only a few seconds (i.e. remembering a phone number just given to you)
    • Working memory: you can remember something that happened recently, but only temporarily
    • Permanent memory (or long-term memory): knowledge is held indefinitely
  • Retrograde amnesia is when you lose access to long-term memories – this is caused by problems in the limbic system
    • This is when family members start to notice something is wrong
  • Everybody goes through cognitive decline, just to a different extent
    • Start to intervene when the individual person notices changes in themselves

More on Alzheimer’s Disease

  • There are 5 areas of study to understand AD:
    • The epidemiology of the disease
    • The imaging of the disease
    • The pharmacologic response to the disease
    • The pathologic findings in the disease
    • The clinical course of the disease
  • The vascular hypothesis states that if you compromise circulation to the brain you are going to end up with a neurological deficit
    • Between ages 22-60, there’s around a 20% decrease in the supply of blood to your brain
  • The epidemiology shows that there’s no greater association with Alzheimer’s disease (or cardiovascular disease) than age
    • After age, the reduced activity of cytochrome c oxidase in the brain is next most heavily associated with cognitive decline
    • Cytochrome c oxidase is the enzyme that’s responsible for oxygen consumption at the cellular level. Without cytochrome c oxidase, the mitochondria have a difficult time creating ATP.
      • Every organism on the planet that uses oxygen to obtain energy relies on cytochrome c oxidase
  • The brain makes up about 2% of our total body weight but consumes about 20% of our total energy expenditure
  • Risk factors for AD:
    • High blood pressure
    • Atherosclerosis
    • Generalized trauma to the brain

Methylene Blue & Other Alternative AD Treatment Methods

  • Francisco has shown in animals that methylene blue (MB) can prevent degeneration in the brain (see this paper and this paper)
    • Methylene blue has the potential to act as a rescue agent during periods of traumatic brain injury (and as a rescue agent for smaller, repetitive blows to the head caused by sports like football and boxing)
      • The problem is there’s no interest from the pharmaceutical companies – they can’t make money because methylene blue can’t be patented
  • Common drugs prescribed for AD such as acetylcholinesterase inhibitors or Memantine are generally ineffective
  • Infrared light may help treat cognitive decline
    • Infrared lights shined on the forehead can go through the tissue and skull (the photons in the near-infrared light range are then absorbed by cytochrome oxidase)
      • This leads to the up-regulation of the mitochondrial enzymatic machinery to produce more energy
  • The ketogenic diet may also help treat/prevent cognitive decline
    • Ketone bodies act as an alternative source for energy in the brain

Additional Notes

  • The heart is like a mechanical engineer; the brain is like an electrical engineer; the liver is like a chemical engineer; the kidney is like an environmental engineer
  • The health of the heart is very closely related to the health of the brain
    • Whatever you do that improves cardiovascular health will also improve brain health
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