#38 - Francisco Gonzalez-Lima, Ph.D.: Advancing Alzheimer's disease treatment and prevention – is AD actually a vascular and metabolic disease?
Francisco Gonzalez-Lima, a Professor of Neuroscience and Pharmacology & Toxicology, explains the vascular hypothesis of Alzheimer's disease as a neuronal energy crisis. He discusses interventions like blood pressure control, ketogenic diets, methylene blue, and near-infrared light to prevent and treat neurodegeneration.
Deep Dive Analysis
15 Topic Outline
Introduction to Alzheimer's Disease and Vascular Hypothesis
Francesco's Background and Functional Brain Mapping
Brain's Redundancy, Parallel Processing, and Control Mechanisms
Critique of the Amyloid Beta Hypothesis in Alzheimer's Disease
Distinguishing Early-Onset vs. Late-Onset Alzheimer's
Hypometabolism and Early Functional Deficits in Dementia
Memory Stages and Differentiating Age-Related vs. Pathologic Decline
The Vascular Hypothesis: Chronic Hypoperfusion and Microvascular Damage
Mitochondrial Respiration and Cytochrome Oxidase in AD Pathology
Methylene Blue: A Metabolic Enhancer and its Historical Context
Challenges and Misconceptions in Methylene Blue Research
Current Standard of Care for AD and its Ineffectiveness
Near-Infrared Light as a Targeted Treatment for Cognitive Decline
Ketogenic Diet and Exogenous Ketones for Brain Energy
Future Research and Applications of Methylene Blue
10 Key Concepts
Functional Brain Mapping
A method to observe behavioral functions reflected in brain activity, using techniques like fluorodeoxyglucose autoradiography, which later led to FTG PET. It allows identification of functional changes in the brain even before structural changes are visible through anatomical imaging.
Brain Redundancy and Parallel Processing
The brain maximizes redundancy and parallel systems, like bilateral symmetry and multiple neural pathways, to ensure information can go through many 'highways and avenues.' This allows for multiple computations, with only converging solutions being acknowledged, providing robust control and resilience.
Thalamocortical System's Role
This system, involving the thalamus and cerebral cortex, is crucial for inhibiting immediate responses, allowing for delayed reactions and computing consequences of actions. The cerebral cortex primarily exerts inhibitory control over subcortical levels, carving out allowed behavioral vectors.
Amyloid Beta Hypothesis
The prevailing but flawed hypothesis that abnormal amyloid beta protein depositions are the central cause of Alzheimer's disease. The guest argues this hypothesis is largely false for common late-onset dementia, though it may apply to rare early-onset familial cases.
Hypometabolism in Alzheimer's
A consistent finding in early Alzheimer's and mild cognitive impairment, where PET scans show decreased glucose uptake and cerebral blood flow in specific brain regions, particularly the posterior cingulate cortex, indicating a neuronal energy crisis.
Vascular Hypothesis of Alzheimer's Disease
This hypothesis posits that the central problem in late-onset Alzheimer's is a progressive neuronal energy crisis caused by impaired blood flow (chronic hypoperfusion) to the brain and impaired mitochondrial respiration. It suggests that improving energy and blood supply can prevent the disease.
Cytochrome Oxidase (Complex IV)
The last and rate-limiting enzyme in the electron transport chain, responsible for reducing oxygen to water and linking cellular respiration to ATP production. It is an inducible enzyme, meaning its functional levels are regulated based on demand, and its inhibition is a key problem in Alzheimer's.
Biphasic Dose Response (Hormesis)
A phenomenon where a substance, like methylene blue, produces opposite effects at low versus high concentrations. At low doses, it can be beneficial (e.g., metabolic enhancer), while at high doses, it can be toxic (e.g., pro-oxidant).
Photodynamic Therapy
A therapeutic approach where a photosensitizing agent (like methylene blue) is injected into tissue, and then specific wavelengths of light are shined on it. The light activates the agent, causing it to produce reactive oxygen species that kill target cells, such as cancer cells or microorganisms.
Ketone Bodies as Brain Fuel
Alternative energy sources for the brain, like beta-hydroxybutyrate, that can be used when glucose transport is compromised (e.g., due to aging or insulin resistance). The brain's uptake of ketone bodies is not compromised with age, making them a beneficial dietary intervention.
11 Questions Answered
Functional studies, like PET scans, show brain activity and metabolic changes, which can detect disease signs early, even before structural changes are visible through anatomical imaging.
The field has largely adhered to the amyloid beta hypothesis, which is based on observations from rare early-onset familial cases, rather than the common late-onset, age-related dementia, leading to a misdirection of research efforts.
Late-onset Alzheimer's, which accounts for over 90% of cases, is age-related with no familial component, and its pathology is not causally linked to amyloid beta deposition, unlike the rare early-onset, familial cases.
The earliest sign is hypometabolism, particularly in the posterior cingulate cortex, which functionally disconnects the main input to the entorhinal cortex and hippocampal formation, leading to memory deficits.
Chronic hypoperfusion (reduced blood supply) to the brain, caused by factors like arterial stiffness, microvascular damage from compensatory high blood pressure, and heart failure, leads to a neuronal energy crisis and is a primary driver of late-onset dementia.
The inability of mitochondria, specifically the cytochrome oxidase enzyme (Complex IV), to efficiently use oxygen and produce ATP due to chronic hypoperfusion or other insults, is a common denominator in various forms of dementia, leading to an energy crisis in neurons.
Methylene blue acts as an electron cycler at low concentrations, donating and accepting electrons to bypass compromised parts of the electron transport chain, thereby facilitating mitochondrial respiration and ATP production.
Methylene blue is an old, unpatentable drug, which disincentivizes pharmaceutical companies from investing in expensive clinical trials for new indications, leading to a lack of FDA approval for these uses.
Near-infrared light photons are absorbed by cytochrome oxidase, photo-oxidizing it and increasing its affinity for oxygen, thereby enhancing mitochondrial respiration and energy production in targeted brain regions like the prefrontal cortex.
As the brain ages, glucose transport becomes compromised, but the uptake of ketone bodies is not affected. Ketone bodies provide an alternative energy source, facilitating mitochondrial respiration and potentially mitigating age-related cognitive decline.
Obese individuals often have down-regulated ketogenesis enzymes due to constant glucose availability. This means their bodies are less efficient at converting stored fat into ketone bodies for energy, making fasting a 'painful transition' and leading to functional starvation at the cellular level despite ample fat reserves.
14 Actionable Insights
1. Adopt Ketogenic Diet/Ketones
Adopt a ketogenic diet or supplement with exogenous ketones to provide an alternative, uncompromised energy source for the brain, especially as glucose uptake declines with age and insulin resistance develops.
2. Practice Periodic Fasting
Practice periodic fasting (e.g., 14-16 hours once a week) to upregulate ketogenic enzymes, enabling the body to use its own fat for energy and reduce hunger between meals.
3. Optimize Blood Pressure
Control high blood pressure, aiming for a systolic blood pressure below 120 mmHg and diastolic below 80 mmHg, to prevent chronic brain hypoperfusion and related cognitive decline.
4. Improve Cardiovascular Health
Actively work to improve overall cardiovascular health, as any improvements in heart and arterial circulation directly benefit brain health and help prevent dementia.
5. Avoid Brain Trauma
Protect your brain from generalized trauma, including repetitive head impacts, as these can lead to forms of dementia by affecting midbrain and upper brain stem function.
6. Facilitate Mitochondrial Respiration
Seek ways to facilitate mitochondrial respiration, as its compromise is a likely common denominator for various forms of dementia and can be a key intervention point.
7. Consider Low-Dose Methylene Blue
Explore low-concentration methylene blue as it can act as an electron cycler to enhance mitochondrial respiration and has shown neuroprotective effects in animal models and improved memory in human studies.
8. Ensure Methylene Blue Purity
If considering methylene blue, ensure it is pharmaceutical quality (USP grade) to avoid toxic impurities like lead, mercury, and cadmium found in lower grades.
9. Explore Near-Infrared Light Therapy
Investigate transcranial near-infrared light therapy, which uses specific wavelengths (e.g., 1064 nm) to photo-oxidize cytochrome oxidase and enhance mitochondrial respiration in the brain.
10. Exercise During Fasting
Incorporate exercise during fasting periods to accelerate the consumption of circulating glucose, further enhancing the body’s ability to build ketogenic enzymes.
11. Methylene Blue for Chemotherapy
For individuals undergoing chemotherapy, consider methylene blue administration before or during treatment to protect the brain from drug-induced mitochondrial respiration side effects.
12. Methylene Blue for Acute Insults
In emergency situations involving acute brain insults like stroke or traumatic brain injury, low-concentration intravenous methylene blue (1 mg/kg) may offer neuroprotection.
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12 Key Quotes
We have not made any significant progress in Alzheimer's disease research. This is the largest failure of the biomedical research enterprise in the world during my lifetime.
Francesco Gonzalez-Lima
The amyloid beta hypothesis... is completely, absolutely false. It has no relationship whatsoever with what we see in the older people that develop dementia.
Francesco Gonzalez-Lima
If you have a brain, you don't want to miss this episode.
Peter Attia
The brain uses the circuits, not just for communication, which is the most obvious function, but to determine and compute outcomes that they are used to guide the other tissues in the body.
Francesco Gonzalez-Lima
The main contribution of this thalamocortical system is to allow us to inhibit behavior. In other words, not to respond in a more immediate, short-term manner.
Francesco Gonzalez-Lima
The compensation for the macrovascular disease may actually be driving part of the damage at the microvascular disease.
Peter Attia
The whole purpose of that chemistry that is done with the foods that we eat is to generate electron donors.
Francesco Gonzalez-Lima
Every organism, including single cells on the planet, that uses oxygen to obtain energy relies on cytochrome oxidase.
Francesco Gonzalez-Lima
It is the, the direction of causality is completely different from the amyloid ideas that the amyloid comes there because of the gene that is abnormal. And then it's creating these cascades that are leading to these changes. No, what we have is these problems with supply of oxygen that happen to the brain and it's high energetic demand.
Francesco Gonzalez-Lima
Methylene blue became the first and for a long time the only treatment for malaria. And this was a major breakthrough in medical research, was in fact the first synthetic chemical used for a medicinal application in the history of medicine and pharmacology.
Francesco Gonzalez-Lima
If you are having Alzheimer's disease and you're in a hospital or being treated by usually neurologists or sometimes psychiatrists, they would prescribe, unfortunately, drugs that have no benefit to the patients but produce adverse effects such as cholinesterase inhibitors and memantine.
Francesco Gonzalez-Lima
If any organ is more liable to influence our eating behavior, it will be the neural tissue.
Francesco Gonzalez-Lima
1 Protocols
Fasting for Ketogenic Enzyme Upregulation
Francesco Gonzalez-Lima- Fast for at least 14-16 hours periodically (e.g., once a week between Friday and Saturday).
- Consume an early meal and a late brunch to facilitate the fasting window.
- Engage in a workout during the fasting period to accelerate the consumption of circulating glucose.
- This process allows the body to build up ketogenic enzymes, enabling the use of body fat for energy and reducing hunger between meals.