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The Truth About Alzheimer’s Disease

In this article I will be investigating the truth about Alzheimer’s Disease. That is, what Alzheimer’s disease is, its symptoms and pathology characteristics, how Alzheimer’s Disease spreads in the brain & how it impairs the brain, the nature of beta amyloids & tau tangles, what causes Alzheimer’s Disease, risk factors for Alzheimer’s Disease, and finally I will cover the preventatives and treatment options available for Alzheimer’s Disease.

What is Alzheimer’s Disease?

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease that first destroys short-term memory and then gradually other cognitive functions. AD is the most common cause of dementia, causing about 60-70 percent of all cases of dementia. About 6 percent of people over the age of 65 are afflicted with AD. And AD is the 6th leading cause of death in the US and other industrialized countries [11].


Most common early symptom of Alzheimer’s Disease (AD) is having difficulty remembering newly learnt information. Symptoms that come after include disorientation, mood and behavioral changes, increasing confusion about places, times, and events; fatigue, apathy, slower movement speed, suspicion of family and familiars, delusions, serious memory loss of long term memories of the past, therefore identity; difficulty speaking, swallowing, walking, and then death.

Healthy Brain Vs Severe AD brain
Alzheimer’s Disease is essentially the rotting of the brain… starting from the Entorhinal cortex & hippocampus. That’s why short-term memories are the first to be affected.

Other symptoms of AD include depression and anxiety. These symptoms are caused by a reduction in hippocampal neurogenesis, which in turn causes the hippocampus of the AD patient to shrink. Usually our level of happiness is influenced by the level of neurogenesis in the hippocampal region of the brain. Such that anti-depressant SSRI medications work by increasing neurogenesis in the hippocampus. So reduced neurogenesis explains why depression and apathy are symptoms experienced in AD. [6]

Furthermore, the extent that tau tangles and amyloid plaques spread throughout the brain correlates with the level of depression in AD. So the level of depression can roughly show how advanced AD is in a patient. Other reasons why AD can cause depression include increased inflammation, alteration of hypothalamic-pituitary-adrenal axis, deficiencies in neurotrophins like BDNF, reduced blood flow perfusion of the brain, reduced metabolism of glucose in brain regions such as the frontal cortex and the anterior cingulate gyrus, increased stress levels, and damage to the serotonin producing brain neurons. [6]

Pathology Characteristics of Alzheimer’s

AD is characterized by the accumulation of amyloid-beta plaques surrounding the outside of the nerve cells, and the formation neurofibrillary tangles of tau proteins inside the nerves of the brain. The development of amyloid-beta plaques and neurofibrillary tangles of tau proteins are known as the 2 main hallmarks of AD. Normally as people age, some amyloids and tau tangles do develop. But AD is distinguished by the abnormally high rate of formation of these hallmarks, and that they spread through the brain in a fixed order. The formation of amyloid-beta plaques and neurofibrillary tau tangles is what scientists pin the blame on for the extreme loss of synapses and neurons seen in AD, which leads to severe memory deficits and cognitive decline.

Generally speaking, amyloid plaques and tau protein tangles begin to form in the brain many years before any cognitive symptoms appear. Perhaps the level of cognitive impairment is dependent on the amount of plaques and tangles that collect in the brain, which explains why starting out there are no cognitive symptoms. The plaques and tangles increase overtime, which is one reason why the AD pathology develops overtime. [4]

One theory about the spread of AD plaques and tau tangles is that they may actually “propagate” from neuron to neuron. Such that highly interconnected neural circuits are more heavily affected, like that of the Entorhinal Cortex (EC). This may be the reason why the EC is the first part of the brain to be affected by AD, and subsequently the hippocampus.[4]

Order of Spreading for Alzheimer’s 

In Alzheimer’s Disease (AD) the amyloid plaques and tau tangles starts forming in the entorhinal cortex, spreads to the hippocampus, then to adjacent brain regions such as the temporal and frontal lobes, and finally the cerebral cortex and the rest of the brain. The aftermath is a total decay of a person’s brain- if they reach such a stage, they will have a level of intellect akin to a baby. And finally the person would usually die because bodily functions shutdown as parts of the brain related to their function rot away.

How Alzheimer’s affects Entorhinal Cortex

Because Alzheimer’s Disease (AD) starts in the Entorhinal Cortex (EC), the EC is the first to be affected by AD. AD impairs the neural connections of the EC region, causing the EC to malfunction.

Before I continue, first know that the entorhinal cortex is a densely interconnected region of the medial temporal lobe that connects to the hippocampus and other brain regions. [4] The EC has functions related to spatial navigation. For example, one region of the EC is populated by grid cells, a special type of neuron that specializes in vector mapping 3D space around the organism. [3].

So AD would cause impairment to the transfer of information through the EC to the hippocampus and other brain regions, impair spatial navigation, harming the 2D map-like spatial navigation of the EC such that a person would become prone to spatial disorientation.

How Alzheimer’s affects Hippocampus

The next target after the Entorhinal Cortex (EC) is the hippocampus. The functions of the hippocampus includes the formation of spatial memories and long-term memories; in other words, the hippocampus is the part of our brain that enables us to learn new things. This process of learning new things may also be known as the “consolidation of short-term memories to long-term memories”. So when Alzheimer’s Disease (AD) starts affecting the hippocampus, the person becomes impaired in the formation of spatial memories and new long-term memories. In other words, an AD patient would experience spatial disorientation and start losing things in their places, become lost more easily, and have a harder time learning and remembering new things. For example, he or she might forget where they just put their car keys, get lost while driving or shopping, forget what they had for breakfast, forget things that they had just done, and the name of the person they had just talked to.

How Alzheimer’s Affects the Rest of the Brain

Then Alzheimer’s Disease (AD) hallmarks spreads to the adjacent temporal and frontal lobes, and then the cerebral cortex and the rest of the brain, thereby disturbing their specific functions such as speech and executive function – like a person’s ability to make judgments.[4][9] The person also will experience an erosion of their past memories, and thereby forget their past history. In this way, an AD patient loses his identity. And eventually die to AD as their brain-dependent bodily functions shut down.

Now let’s talk about the hallmarks of AD; what seem to be the driving factors for the Alzheimer’s pathology.

What are Beta Amyloids?

One theory of AD pathology is that the Amyloid-β plaques keep accumulating in the brain to cause AD. But what are Amyloid-β (Aβ) plaques?

Beta amyloid is a small peptide or protein that has a long, slender, fiber-like structure. Fibril for short. 

A Stick & Ribbon model of Beta Amyloid 42 molecule
A Stick & Ribbon model of Beta Amyloid 42 molecule.

Well, Aβ are peptides that make up the majority of an Aβ plaque. Other than a core of amyloid, these plaques are also composed of fragmented and decaying nerve terminals. What usually happens is that if the plaque gets too big, it starts pushing on the nerves around it, causing miscommunication and eventually damage to those nerves.

Amyloid-β is a protein that neurons secrete. Even healthy people’s brain secretes Amyloid-β. But the problem is that these amyloid proteins are not cleared away properly in AD. That’s why Amyloid-β keeps building up in the brain of AD patients to form up the plaques known to AD. Amyloid-β plaques do build up outside of the cell, and blocks neuronal communication.

But there is a reason why these proteins are secreted. Amyloid-β by another school of thought is thought to be protective, reparative, restorative and a defense mechanism against AD. So in AD the problem is not that these proteins exist, but that these proteins aren’t being cleared away properly.

Where do Beta Amyloids Come From?

Beta amyloids are produced when something called the “Amyloid Precursor Protein” (APP) is sliced by a enzymes called beta (β) secretase and gamma (γ) secretase. So theoretically an increased activity of β and γ secretase increases the production of β amyloids from available APP, thereby increasing the risk of developing Alzheimer’s Disease (AD). But this depends on the type of Beta Amyloid (Aβ) produced. That’s because there are many different types of Aβ, with Aβ40 being relatively benign, and Aβ42 being quite destructive.

The genes that are associated with an increased risk for AD encodes the APP protein. And APP is ubiquitously found in neural and non-neural cells. 

Types of Beta Amyloid

Beta amyloids don’t refer to only one homogeneous molecule; rather, there are many different types of Beta amyloids. And the number used to differentiate the types of Aβ simultaneously refers to the length of the Aβ peptide, or how many amino acids the Aβ peptide is made up of. So for example, a Aβ40 is composed of 40 amino acids.


Aβ40 is the most common species of amyloid, and is relatively benign. Aβ40 does not lead to plaque formation, and in fact protects against the plaque formation caused by the deposition of Aβ42 in the brain. [16]


On the other hand, Aβ42 enhances the formation of oligomers, which is detrimental to neuronal health. What happens is that Aβ42 initially forms microscopic deposits in the brain. These deposits are diffused plaques- diffused meaning not fibrillary. Then the diffused plaques trap strands or “fibrils” of Aβ, thereby becoming a fibrillary plaque. Which then causes localized inflammation around those fibrillary Aβ plaques. The inflammation is characterized by an increased level of white blood cells such as microglia and astrocytes, and those white blood cells release free radicals as a part of the inflammatory response. This causes collateral damage by reducing the number of synaptic spines (projections), harming the surrounding neurons, and eventually killing those neurons. [16]

Amyloid-β Oligomers

Aβ molecules can group together to form flexible soluble oligomers. Oligomers are a complex of molecules that are made up of a few repeating units. The theory that accumulating Aβ causes AD also states that those misfolded oligomers of amyloid can act as seeds, causing other molecules of Aβ to form misfolded oligomers. Like this, Aβ oligomers, a.k.a. amyloid plaques, may cause a chain reaction for inducing brain dystrophy like a prion infection.

Oligomers vs. Plaques

Oligomers of Aβ can be more damaging that plaques of Aβ, because fibrillar plaques have much less Aβ surface area to neuronal membranes.

In contrast, oligomers are higher in number, and can diffuse or pass through the synaptic clefts of a neuron, and cause damage from within. So oligomers are more likely to cause neuronal/synaptic dysfunction. Indeed, the quantity of soluble oligomers correlate better with cognitive decline than plaque counts. [12]

Monomer of Aβ

Single molecues of Aβ (monomeric Aβ) are digested or “broken down” by an enzyme called “Insulin-Degrading Enzyme” (IDE). But oligomeric Aβ is resistant to be broken donw by IDE [12]

Amyloid Plaques

illustration of beta amyloid plaques and tau tangles
For the brain afflicted with Alzheimer’s disease, the beta-amyloid proteins tend to clump together to form plaques (the brown ones in the image). These plaques crowd the spaces between neurons and disrupt their function.
Likewise, tau proteins tangles clump together inside of the neurons and by that harm the synaptic communication between neurons.

Amyloid plaques tend to be a heterogeneous mixture of 37-43 Aβ peptides. One function of a amyloid plaque is to sequester the toxic Aβ oligomers that destroy the neurons that it interacts with. Although amyloid plaques cause the surrounding neurons to become dystrophic, it overall reduces the damage that separate oligomers of Aβ can cause. [12]

Initially it was proposed that amyloid beta plaques in general were the main driving force of AD. So accordingly what increases the amount of beta amyloid theoretically would be the main cause of AD. For example, in one study[15] scientists found that mutations in the presenilin 1, presenilin 2, and amyloid beta-protein precursor protein genes increases the extracellular concentrations of Aβ 42(43). Note that mutations in these genes are all linked with the incidence of  familial Alzheimer’s Disease. So this indicates that gene mutations that increase the production Aβ may cause AD. Theoretically, what stops the clearance of Aβ from the brain could also cause AD.

Note that the type of beta amyloid makes the poison. For example, beta amyloid 40 is relatively benign. Whereas beta amyloid type 42/43 is rather toxic to the neurons in the brain.

Alternative Functions of Amyloid-β

The Aβ oligomers are toxic to nerves[12], not necessarily single independent units of Aβ itself. Some studies even show that abundant amyloid depositions in humans and mice brains do not necessarily show memory deficits or neuronal toxicity.

In fact, the presence of separated Aβ molecules may have a beneficial effect on the surrounding nerves. Before I elaborate, note that an absence of Aβ is not observed to cause a loss of brain function. But if present, Aβ (specifically Aβ40) functions as a highly potent antioxidant that protects against free radical oxidative stress [13]. And beta amyloid plaques can be “beneficial” by means of damage reduction, sequestering the damaging Aβ oligomers that cause neuronal synaptotoxicity.

Monomeric Aβ vs Oligomeric Aβ

In another study [14], Aβ1-40 monomers are seen to be beneficial by acting:

“as a natural antioxidant molecule that prevents neuronal death caused by transition metal-induced oxidative damage… Monomeric Abeta1-40 inhibits neuronal death caused by Cu(II), Fe(II), and Fe(III) but does not protect neurons against H2O2-induced damage. Monomeric Abeta1-40 inhibits the reduction of Fe(III) induced by vitamin C and the generation of superoxides and prevents lipid peroxidation induced by Fe(II). Abeta1-42 remaining as a monomer also exhibits antioxidant and neuroprotective effects. In contrast, oligomeric and aggregated Abeta1-40 and Abeta1-42 lose their neuroprotective activity. These results indicate that monomeric Abeta protects neurons by quenching metal-inducible oxygen radical generation and thereby inhibiting neurotoxicity. Because aggregated Abeta is known to be an oxygen radical generator, our results provide a novel concept that the aggregation-dependent biological effects of Abeta are dualistic, being either an oxygen radical generator or its inhibitor.”

So monomeric Amyloid Beta acts like an antioxidant for free radicals generated by different types of metals that may start to gather in the brain in an unhealthy way. Usually the increased concentration of different types of metals in the brain occurs overtime- that may be one reason why cognitive decline is observed with advanced age. The different types of metals that gather in the brain include heavy metals such as lead, mercury, and cadmium; and other metals like aluminium.

Pathology of Tau Tangles

What is tau? What is the function of tau?

Tau is a protein found abundantly in axon of neurons of the Central Nervous System (CNS). Tau “stabilizes” or holds together microtubules in the neuron. Microtubules made up of polymers of tubulin, and microtubules act as a part of the cytoskeleton that provides the structure to a neuron. Microtubules have other functions, such as acting as transport routes for moving organelles, proteins, neurotransmitters, nutrients & fuel, waste material, etc. If the microtubules shutdown, that would be similar to the main highways of a city shutting down, trapping the traffic in place and thereby causing chaos. If the microtubules stayed offline, then the neuron would eventually die. And one way that a microtubule can become disfunctional is if the tau holding it together becomes tangled.

What is a tau tangle & How they form?

In Alzheimer’s Disease, the Tau proteins inside the neuron can become tangled (a.k.a. Neurofibrillary tangles) via hyperphosphorylation. These tau tangles accumulate in the neuron, until the neuron dies.

The interesting thing is that Tau tangles are not only isolated to Alzheimer’s Disease. Tau Tangles can also be seen in Huntington Disease, Parkinson’s Disease, and nearly all diseases related to neurodegeneration.

tau protein on microtubules tangle and clump
A diagram depicting the degeneration of Tau Proteins that stabalize the microtubules of a neuron. From diseased neurons, the microtubules disintegrate, causing the tau proteins to tangle and clump together.

And just as amyloid-beta (Aβ) replicates like prions, tangled tau proteins also replicate by coming in contact with normal healthy tau proteins. But tangles in Tau protein are purely neurotoxic, whereas the presence of certain monomeric Aβ may have a protective effect on nerve cells. Although the accumulation of beta-amyloid blocks neural communication, the spread of tau tangles leads to the deterioration of the brain tissue. Misfolded tau proteins cause a severe loss of neurons, synapses [1], dendritic spine density[2] and other brain cells. Know that dendrites are signal receivers for neuron, and dendritic spines are projections, like a tree’s branches, for improving receptivity of dendrite.[2]

As for how tau tangles spread, scientists observed that clumps of tangled tau protein are easily taken into neurons growing in the petri dish, and then inside those neurons, the tau clump act like seeds which cause other tau protein molecules to misfold and form new tangles. When tau tangles are injected into the brains of healthy mice, the clumps of tangled tau protein spread across the synapses into interconnected neurons, and from there to adjacent regions.

Tau arranges based upon the number and strength of connections that a brain region has. That means the more interconnected a certain brain region is, the more tangled tau protein accumulates in those interconnected areas.

Tau tangles are thought to be toxic to the synapses, which are the connections between neurons. Tau’s toxicity to the synapses could explain the widespread loss of synaptic connections overtime in AD. This reduction in synaptic connections is closely correlated with cognitive decline; the more synapses are destroyed, the worse a person’s cognition becomes. Given this fact, neurofibrillary tau tangles may be a better indicator of the progress of Alzheimer’s Disease progression than plaques. [4]

Risk Factors for Alzheimer’s Disease

Risk factors for Alzheimer’s Disease includes chronic neuroinflammation, carrying the APOE-ε4 gene, exposure to heavy metals & aluminium, and aging in general.

Chronic Inflammation as a Risk Factor for Alzheimer’s

One main major risk factor for the occurrence of Alzheimer’s Disease is chronically elevated inflammation of the brain. In fact, it is observed that as AD progresses in a patient, their level of constant brain inflammation increases.

The AD brain shows an increased presence of activated microglia, reactive astrocytes, proinflammatory cytokines, acute phase proteins, and activated complement proteins compared to controls. [5]

Know that microglia are a type of white blood cell or macrophage that eat up the dead neurons & waste materials in the brain. Microglia cluster around amyloid plaques. As the severity of AD increases, so does the number of Aβ plaques. And in response, inflammation and active white blood cells such as microglia also increases. This increase in inflammation worsens the situation because that means that the production is increased for pro-inflammatory cytokines and other neurotoxic factors, such as reactive oxygen species. [5] Like a snake swallowing its tail, the rise in inflammation damages the surrounding neurons and other brain cells, leading to their death, and the presence of those dead neurons turns the immune system on higher. 

The inflammation also makes AD progress faster. In fact, there have been studies [5] showing that neuroinflammation is a part of a process that spreads the corrupted tangles of tau proteins, thereby speeding up the progression of AD throughout the brain. The increased spreading of tau tangles happens because inflammation increases the presence of active microglia. And its the microglia that help to spread the tau tangles throughout the brain. And when [5] microglia is absent or depleted in mice models of AD, it is observed that the spreading of phosphorylated Tau (the type that tangles) is heavily reduced.

My conjecture is that like other macrophages, microglia swallow the tangles tau proteins, but is unable to digest all of it, and ends up depositing it other parts of the brain.

Another thing to consider is that amyloid proteins are secreted in response to head/brain injuries like concussions.

APOE-ε4 Gene as a Risk Factor for Alzheimer’s

People who are carriers of the APOE-ε4 gene are genetically at risk for Alzheimer’s Disease (AD). In fact, having the epsilon-4 allele of the APOE gene is the strongest genetic risk factor for late-onset AD. People who carry 1 copy of the APOE-ε4 gene have a 3 fold increased risk of AD. And people who carry 2 copies of the APOE epsilon-4 allele are more than 10 times at risk for acquiring AD, which is about a 50-90% chance.

People with the APOE-ε4 gene tend to have the most Amyloid build up in there brain, and to have tau abnormalities in the brain earlier on in life.

One study[3] investigated the consequence of carrying the APOE-ε4 gene in young adults. The young adults who carry this gene are observed to have a smaller number of grid-cells in their Entorhinal Cortex (EC). The grid cells are required for 2D vector navigation, which explains why those young adults were observed to have altered navigational behavior in a virtual environment. To give context, the scientists were testing the spatial ability of the test subjects by tasking them with the navigation of a 3D virtual environment on a computer. An observation made by the researchers is that these young adults exhibit increased hippocampal activity to compensate for the spatial memory impairment caused by the APOE-ε4 gene induced reduction of of grid-cells. Which is cool because it shows us that our brain can adapt to limitations, such that if a part of the brain doesn’t working properly, then other parts of the brain may function in its place- albeit not in the same way or capacity.

Aluminium Exposure as a Risk Factor for Alzheimer’s

High exposure to aluminium is a risk factor for acquiring Alzheimer’s disease. Normally, aluminium is a benign metal that can be commonly found in one’s environment. Additionally, aluminium has a low bioavailability. But if the body’s content of aluminium becomes high besides the low bioavailability, then aluminium can pose a problem given that it is toxic to neurons. People who are exposed to high levels of aluminum show symptoms of Alzheimer’s Disease.

Certain types of aluminum can cross into the brain through the blood-brain barrier, the choroid plexuses, and the nasal cavity. “Some factors, such as the increasing of the blood-brain barrier permeability, citric acid and parathyroid hormone (PTH), and vitamin D, can promote aluminum to enter the brain. But the redistribution of aluminum out of the brain is slow, so aluminum can be deposited in the brain for a long time.” Due to this fact, the human brain content of aluminum usually increases with age, overtime. Additionally, aluminium exposure itself contributes to the permeability of the blood brain barrier. [7]

Another way that aluminum can enter the body is through subcutaneous injections containing the aluminum hydroxide. When this chemical is injected in young male mice, it induced apoptotic neuronal death in motor neurons in the spinal cord and motor cortex, accompanied by degraded motor function [17]. Similar effects can be seen in young soldier who had to take too many vaccines for going oversees; this occurrence has been known as Gulf War Syndrome. Although I personally advocate for the usage of vaccines, this issue makes me wonder if there are alternative vaccines that use something other than aluminum hydroxide that works as an adjuvant for boosting the immune system. Adjuvants are used in order to help the immune system produce antigens for long-term immunity against a disease.

Aluminum is found to deposit in the cortex, the cingulate bundles, the corpus callosum, and the hippocampus. As a result, these brain regions are negatively affected and causes associated cognitive deficits, such as in executive function, learning and memory. And when aluminium is found in the brain, they are usually concentrated in the senile or “amyloid” plaques and neurofibrillary tau tangles. My conjecture is that either the plaques serve to sequester the neuron-killing effects of aluminium, and/or that aluminium ends up interrupting the function of tau proteins by causing them to tangle. [7]

Exposing the brain to aluminum causes similar hallmarks of AD, which is the formation of amyloid plaques and tau protein tangles. Aluminum exposure also causes apoptosis of neurons, the abnormal swelling of mitochondria, and the thinning of myelin sheaths that cover the axons- resulting in poorer neuronal communication. [7]

But not all AD patients have high levels of aluminum in their brain. So this shows that aluminum is only one out of many possible causative factors for AD. And it could be that Aluminum only speeds up the onset of Alzheimer’s Disease, or overall age-related dementia. Metaphorically like how being splashed with cold water makes a person’s pre-existing fever worse.

Preventatives & Treatment options for Alzheimer’s Disease

Preventatives and treatment options for Alzheimer’s Disease include exercise, other means for increasing BDNF and Neurogenesis in the brain, eliminating tangled tau proteins with antibodies, and caffeine.

Exercise benefits via BDNF and Neurogenesis

In one study, a mouse model of Alzheimer’s Disease showed that exercise improves memory by increasing the level of neurogenesis in the hippocampus, and by increasing the level of Brain Derived Neurotrophic Factor (BDNF). BDNF is a growth factor that signals the neurons to survive and grow. So the study suggests that these benefits derived from exercise help in preventing Alzheimer’s Disease. Normally AD causes an extreme loss of synapses and neurons, but exercise works in the opposite way to increase the number of synapses and neurons and improve their functions. [1]

In fact, aerobic fitness is one factor that increases the volume of the Entorhinal Cortex (EC). Perhaps that’s one more reason why exercise is a factor that lowers the risk for acquiring AD, because it strengthens the part of the brain where the AD originates from.

One study, exercise is also shown to decrease the hyperphosphorylation of tau proteins. Hyperphosphorylation is the process that converts a normal tau protein into a tau tangle. [18]

Physically speaking, hyperphosphorylation causes a tau protein to be bond to an excessive number of phosphor groups. Hyperphosphorylated tau proteins end up detaching from the microtubules, and then becoming tangled into other hyperphosphorylated tau proteins. This is causes the formation of neurofibrillary tangles, which look like tangles of hair under a microscope.

Note that scientists speculate that hyperphosphorylation is actually one of the cell’s mechanisms for slowing down or stopping cell division. If these mechanisms fail, you usually end up with cancer.

Targeting the Tau

Some scientists theorize that stopping the spread of tau could stop the progress of neurodegeneration. Because tau tangles are toxic to synapses; so stopping the spread of tau would stop the spread of toxicity and reduce the progress of neurodegeneration

And so scientists are developing treatment options with the purpose of stopping the spread of tau proteins. One option is to use antibodies to bind to the tau and prevent the tau proteins from spreading.

One antibody that targets the tau protein is known as ABBV-8E12, which binds to the tau clumps outside of the cell. Researchers have found that this antibody is able to block the clumping of tau in neurons in vitro, and prevent tangle formations in mice. And the researchers also found that this indeed alleviated the cognitive deficits in the mice, showing that the tau protein is indeed harmful for cognition.

A phase one trail of the tau binding drug was tested on 30 people with progressive supranuclear palsy (PSP), which is a pathology that targets and concentrates the formation of tau tangles in the brain stem. A phase two trial of the tau binding drug will be done with Alzheimer’s patients, and is expected to finish around 2021

There are also other novel compounds that have the ability to stop the spread of tau, like cambinol.

Cambinol works by inhibiting an enzyme called nSMase2. nSMase2 has the function of releasing vesicles that tau uses to cross synapses. So inhibiting this enzyme would help to slow down the spread of tau tangles. The problem is that tau proteins have more than one way to transfer from one cell to another. Another problem is that targeting and stopping an enzyme from functioning also means that the enzyme will no longer perform its duties, which we may or may not have knowledge of. That’s why targeting the tau specifically with an antibody is superior because it does not interfere with the physiological functions of the cell.

Finally, just as targeting the amyloid-β alone does not stop Alzheimer’s Disease, targeting the tau protein tangles alone may not stop Alzheimer’s Disease, because AD also involves inflammation, microglial-cell dysfunctions, and other pathologies. And so a drug or treatment may have to target several causes of Alzheimer’s Disease to treat it successfully. [4]

Note that it is not the same for the amyloid. Getting rid of amyloids within the brain with pharmaceutical drugs do not cure AD, and does not even help AD. The patients become worse off cognitively, so perhaps that shows AD itself is not a bad thing, but a by-product or an adaptive reaction to a bad thing.

Caffeine’s Neuroprotective Affect Against Alzheimer’s

Not only does caffeine show protective effects against neurological disorders and cognitive decline, but also against Alzheimer’s Disease as well. In fact, there have been many studies that observe that the regular consumption of caffeine is inversely correlated with the incidence of AD. The main mechanism of caffeine involves the non-selective blockage of adenosine receptors, which causes the amount of adenosine in the plasma to rise. In the brain, adenosine acts as a neuromodulator that is able to control the excitability of neurons, and able to influence the activity of non-neuronal cells such as astrocytes and microglia. Caffeine can also exert a neuroprotective effect against Aβ toxicity through the specific blockage of the A2A subtype adenosine receptor. The A2A adenosine receptor modulates the inflammatory process, so when caffeine blocks this receptor, the level of inflammation becomes milder in the brain. Blocking the A2A adenosine receptors reduces the formation of of Aβ plaques and neurofibrillary tangles. [8]

Alzheimer’s Disease is Type 3 Diabetes for the Brain

So there exists a school of thought where scientists claim that Alzheimer’s Disease (AD) is like type 3 Diabetes for the brain. That’s because for many AD patients, their brain neurons experience a high level of insulin resistance. This causes the inability of brain neurons to metabolize glucose as a fuel source. The result is that the AD brain experiences a fuel shortage, and therefore the neurons can no longer function without an energy source to drive them.

For this reason you’ll see in AD patients that their brain is shrinking- because neurons are starved for fuel and are atrophying, and eventually dying off one-by-one.

Also consider that the brain has a high level of energy consumption. The brain accounts for about 2% of the body, but accounts for about 20-25% of the body’s energy consumption

So because of the brain’s energy demand, an interruption to brain’s fuel supply is devastating. Typically,  AD patients have up to 45% reduced utilization of glucose. 

Type 2 diabetes is also a risk factor for AD and cognitive decline, which makes sense given that the brain is so dependent on fuel utilization. Likewise, chronically high insulin levels is a major risk factor for AD.

Amyloid plaques are cleared by an enzyme called “Insulin Degrading Enzyme” (IDE). So if there is a lot of insulin circulating in the blood stream, then this enzyme does not target the amyloid beta proteins in the brain

Amyloid inhibits pyruvate dehydrogenase enzyme. This enzyme is the connection between glycolysis and the crebs cycle, which are 2 ways to produce energy from glucose. Our cells convert glucose to pyruvate through the process of glycolysis, then pyruvate converts to Acetyl Co-A, which then gets “burned” or oxidized to produce energy through the crebs cycle. So amyloid is inhibiting the metabolism of glucose in the brain through its enzyme inhibition. But there exists AD patients without that many amyloid plaques.

Amyloid may inhibit the pyruvate dehydrogenase enzyme in order to shut off glucose consumption by the nerve cells, because glucose metabolism over a long period of time (especially on the american SAD diet that consists of frequent snacking and consumption of glucose) damages the mitochondria severely. And instead this glucose is sent to the pentose phosphate pathway to help neurons to restore and regenerate.

So other than glucose, the brain can run on ketones, which doesn’t run into the same metabolic blocking that glucose runs into with AD insulin resistance. So AD neurons that can’t uptake glucose, can intake ketones instead. And thereby improve cognition in AD patients. So ketone levels can be increased by diet or by supplementation. Ketones can replace up to about 60% of the brain’s energy


Learn More About Alzheimer’s Disease


  1. A Brain Boost to Fight Alzheimer’s Disease
  2. Lost Memories Found
  3. Reduced grid-cell–like representations in adults at genetic risk for Alzheimer’s disease
  4. Ways to stop the spread of Alzheimer’s disease
  5. Neuroinflammation is increased in the parietal cortex of atypical Alzheimer’s disease
  6. Handbook of Depression in Alzheimer’s Disease
  7. 2018 Book of Neurotoxicity of Aluminum
  8. 2018 Book of The Adenosine Receptors
  9. Video: What is Alzheimer’s Disease? [YouTube]
  10. The Alzheimer’s Antidote: Can we prevent Type 3 Diabetes? | Amy Berger
  11. Amyloid β oligomers (AβOs) in Alzheimer’s disease. [J Neural Transm (Vienna).]
  12. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide [Nat Rev Mol Cell Biol.]
  13. Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems. [Biochemistry]
  15. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. [Nat Med.]
  16. Generation of Alzheimer Disease-associated Amyloid β42/43 Peptide by γ-Secretase Can Be Inhibited Directly by Modulation of Membrane Thickness [J Biol Chem.]
  17. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration [J Inorg Biochem.]
  18. Effect of treadmill exercise on PI3K/AKT/mTOR, autophagy, and Tau hyperphosphorylation in the cerebral cortex of NSE/htau23 transgenic mice. [J Exerc Nutrition Biochem.]

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