Alzheimer's has a decade long phase of Glucose hypo-metabolism (reduced metabolism) in the brain. Ketone body (a special derivative of fat) metabolism remains unaffected and intact.
Sub cortical (the root level, reactive non-thinking base of the brain) damage precedes Alzheimer's.
Beta-amyloid protein (an abnormal cell waste product) is toxic.
Micro glia (immune function cells in the brain) inflame and degrade neurons (nerve cells) and astrocytes (nerve support cells.)
Impaired astrocyte function degrades cognitive function from damaged energy metabolism for the neuron (nerve cell) and decreased inhibition of micro glia action to destroy nerve cells and their connections.
Mitochondrial DNA is inherited from the mother in humans.
Glucose hypometabolism (inability to use glucose for energy) is more severe with 2 demented parents, intermediate with only demented mother and least with only demented father.
Glucose hypometabolism leads to less hexokinasei (an enzyme used in glucose metabolism) binding of mitochondrial anion channels (energy requiring revolving door of the mitochondrial wall) which prevents escape of untreated and damaging ROS (reactive oxygen species analogous to rust particles). More cellular ROS activates oxidative stress (rust) and inflamasomes (chemical committee or molecule that degrades cells). Beta-amyloid in the mitochondria increases ROS production that can escape from the mitochondria into the cell and cause inflammation.
APP or amyloid precursor protein is produced by neurons, astrocytes and microglia. The latter 2 can rapidly produce APP when stimulated by neuronal injury.
When cleaved (separated into 2 parts) to an active form by alpha secretase (enzyme= protein that alters another protein), it is soluble and neuroprotective (useful during development)
When alternatively cleaved by beta secretase (an enzyme) it is soluble but not neuroprotective. Further action by gamma secretase (enzyme) makes soluble beta amyloid and a generator of ROS and inflamasone activation. With increasing and concentrated amounts, beta amyloid precipitates in cells and forms non-soluble aggregates.
Dementia correlates best with soluble Beta amyloid which is the toxic form. The precipitates and plaques of beta amyloid are only non-soluble residues of the invisible soluble toxins that have already damaged the cell and brain. (Analogous to radioactive precipitates or aggregates after a nuclear blast, the damage is done and only the contamination remains)
This leads to oxidative stress, release of stimulating glutamate (a brain chemical that
activates, energizes or over energizes) which causes extra synaptic NMDA receptor
activation and synaptic loss. (Analogous to a power surge that damages the function)
The damage by soluble beta amyloid (which blocks glucose uptake, oxygen uptake and astrocytes mitochondrial depolarization producing a dead battery/mitochondria) is blocked or prevented by addition of pyruvate, the end product of glucose metabolism in the cell outside of the mitochondria which next becomes fuel for the mitochondria.
Beta hydroxybutyrate, a ketone energy chemical derived from medium chain triglycerides such as coconut oil, also blocked soluble beta amyloid damage.
Energy supplied, in the form of pyruvate, prevented cognitive decline (synaptic signaling or long term potentiation and synaptic loss) without reducing amyloid precipitates and plaques in a mouse model of Alzheimer's.
Conjecture: since a small level of supplemental energy 4mM of beta hydroxybutyrate like pyruvate 5mM inhibits soluble beta amyloid damage; and because beta hydroxybutyrate binds NLRP3 to prevent activation of the inflamasone which leads to cell death; improved metabolic health represented by ketosis after 10 hour fast, high BDNF levels (which amplifies metabolism and promotes neuroplasticity and repair) plus low glycemic Mediterranean diet supplemented with MCT and Coconut oil (which makes beta hydroxybutyrate and improves cell membrane function and integrity) plus DHA 900 mg (the omega 3 fatty acid in the brain that demonstrably
improves language acquisition in the young, improves short term memory by 50% in mild cognitive impairment, a precursor of dementia in the elderly and also improves measurable synaptic and phospholipid membrane functions) would treat both 1.the hypometabolic glucose energy deficit in the cell (ketone such as beta hydroxybutyrate for mitochondrial fuel) and 2. Beta hydroxybutyrate blocks NLRP3 and damage from increased ROS (activation of NLRP3) that results from reduced glucose use for energy in the cell fluid leading to expulsion of ROS from mitochondria.
Dementia may begin in the subcortex (the brain stem or root level of brain below the cortex) first, an antegrade degeneration originating in the brainstem (root) and secondarily affecting the brain cortex (tree)
The brain stem sends noradrenergic (a stimulant chemical) projections to the cortex. The same system responsible for heart rate variability, indirectly; is directly responsible for beta adrenergic receptor (the target of noradrenalin and adrenalin) stimulation that suppresses the activity of inflammatory transcription factors (gene switches in the DNA) causes alterations in nuclear localization of proteins (chaperones that help fold proteins into their optimum shape for action), and induces gene expression via cAMP-response element binding protein activation (creb =an active protein made by DNA with help from chaperone proteins) which are neuroprotective and anti-inflammatory. 1. These creb proteins increase expression of neurotrophic substances including BDNF (brain derived neurotrophic protein),GDNF (glia derived neurotrophic protein) and nerve growth factor. The absence of these factors are
permissive for dementia. 2.Noradrenergic enhances metabolism. It promotes glycogenolysis the release of glucose from liver and muscle stores. It also enhances the rate that NAD and cytochrome can increase the production of ATP with increased demand or intensity of movement or cellular work.
