Part I – Beware of what appears to be logically obvious
A lot of things in our world appear obvious only to be proven wrong by experimentation. For most of us, the world is flat – it looks flat, it feels flat. A flat earth is the most obvious hypothesis based upon our everyday experience. Likewise, the sun rotating around the earth feels more right than the earth spinning on its axis and simultaneously rotating around the sun. Despite knowing different, we still use terms like the “rising” or “setting” sun. The sun does not rise or set – the earth rotates.
Take a moment and think about that for a minute. It is fantastical. We take it for granted because scientists of old proved that the world could not be flat and that it was not possible for the sun to be rotating around the earth. Information that falsifies a previously held belief is how science and knowledge evolves. It forces scientists to re-evaluate not just the new information, but all of the old information as well and then consolidate the entirety of information on a topic into a hypothesis that is consistent with all of the data. Unfortunately, this rarely happens.
To access the FREE seminars with full presentations and videos please visit Dr. Goodenowe’s resource site here. This is the article for Lecture 4, 5, and 6 – Cognitive Impairment and the True Cause of Alzheimer’s Neuropathology – What Everyone Needs and Deserves to Know of Breaking Alzheimer’s – The Definitive Lecture Series. The videos for these lectures are:
Lecture 4 – The Biochemistry of Impaired Cognition
Lecture 5 – The Biochemistry of Neurofibrillary Tangles
Lecture 6 – The Biochemistry of Amyloid
The longer that people collectively agree on a particular perception, the harder it is to convince them otherwise. Furthermore, they will seek out information that supports their belief and ignore or suppress information that contradicts their belief. They will even believe bizarre explanations for why certain observations or data do not support their belief. Science is not supposed to be practiced this way, but scientists are still people. They have careers. They have families. They have bills. They work for organizations that have financial commitments and investors and scientific infrastructure. Administrators and investors are not scientists and they rely on scientists’ opinions. Nobody wants to look or feel stupid. Ignorance is not stupidity. Naivete is not stupidity. Unknowingly being manipulated is not stupidity. Nobody should feel stupid for not knowing what you are about to read in the following paragraphs or view in the accompanying three videos. Angry? Maybe. Also, it is unfair to blame most doctors and scientific researchers – they are just doing their jobs – and their job is not to solve the big picture. Most are tasked with specific finite subsections of the whole and will live their entire lives in one area. You cannot blame the electrician for an incorrectly designed building.
Unfortunately, the public, big-picture, side of science and medicine is mostly propaganda interspersed with just enough valid science to create a veneer of credibility. The higher the stakes, the louder the propaganda. In all of medicine, there is no greater unmet need than the development of effective treatment and management strategies for “Alzheimer’s Disease”. Decades of research, billions of dollars of investment, and thousands of careers have been built on a false hypothesis: Amyloid plaques and neurofibrillary tangles are neurotoxic and this toxicity is the underlying cause of the neurodegeneration and cognitive impairment commonly observed in persons with high levels of these neuropathologies in their brain. Based upon this false hypothesis, the public has been led to believe that the removal of these neurotoxins will prevent the neurodegeneration and cognitive impairment associated with Alzheimer’s disease. This is an unconscionable lie.
Ultimately the cause of all death and disease is ignorance and inaction. I can help you with the former, but the latter is up to you. In the following paragraphs and accompanying videos, I will expose the absolute absurdity of the narrative that amyloid and neurofibrillary tangles are the underlying cause of impaired cognition.
Part II – A brief history of why science jumped to an obvious, but false, conclusion
In 1906, Dr. Alois Alzheimer examined the brain of a 55-year-old female patient who had been suffering from dementia for at least 5 years prior to her death. Dr. Alzheimer discovered specific neuropathologies that now bear his name: extra-neuronal amyloid deposits and intra-neuronal neurofibrillary tangles. Throughout most of human history, senile dementia (which occurs after age 65) has been considered a natural part of the aging process. It was not until the 20th century that scientists began to investigate and hypothesize regarding the cause of senile dementia more seriously. At the turn of the century, Dr. Alois Alzheimer was the first to discover and associate certain neuropathologies with dementia.
Alzheimer’s disease as described by Dr. Alzheimer was first recognized as a rare type of pre-senile dementia. It was not considered a cause of senile dementia. Most researchers believed that hardening of the arteries (atherosclerosis) was the primary cause. It was not until the 1960s that senile dementia began to be classified into subtypes. In the 1960s, it became clear that many older persons with the classical representation of senile dementia had neuropathology indistinguishable from pre-senile Alzheimer’s disease when examined post-mortem. This condition was then called senile dementia of the Alzheimer’s type. Today, most cases of senile dementia are classified as either Alzheimer’s, vascular, Lewy body, or frontotemporal lobe dementia. Most dementia cases consist of mixed pathologies, not one or the other. Some have hardly any neuropathology, which means that assigning the causation of dementia to a particular neuropathology has always been illogical.
Understanding the role of neuropathology in the etiology of dementia has been hindered by the obfuscation of certain words and definitions. The terms “Alzheimer’s pathology”, “Alzheimer’s disease”, and “dementia of the Alzheimer’s type or Alzheimer’s dementia” are often used interchangeably. This is made worse because Alzheimer’s disease and Alzheimer’s dementia are abbreviated as “AD”. These three “Alzheimer’s” terms have three different meanings.
“Alzheimer’s pathology” is the purest of these terms and refers to the direct measurement of amyloid plaque or neurofibrillary tangle density in a brain region. It is not an interpreted value – it is what it is.
“Alzheimer’s disease” is the neuropathological classification of a person as determined by a neuropathologist. Following an autopsy, a neuropathologist will review the neuropathological data across multiple brain regions and using one of several different neuropathological scaling systems make a collective determination of the severity of Alzheimer’s pathology – none, low, moderate, severe. This is purely neuropathological – there is no consideration made as to the clinical state of the person prior to death.
“Alzheimer’s dementia” is the combination of two separate clinical determinations. First, there must be a determination of dementia. Dementia is not a pure measurement either, it is a clinical classification. A doctor will review a variety of cognitive test results and in some cases caregiver interview data using various cognitive scaling systems and make a collective determination of the severity of cognitive impairment – none, mild, moderate, severe. A person who has reached a threshold of cognitive impairment sufficient to warrant a diagnosis of dementia and who has reached a threshold of Alzheimer’s pathology sufficient to warrant a diagnosis of Alzheimer’s disease is classified as having dementia of the Alzheimer’s type, or Alzheimer’s dementia.
Accordingly, Alzheimer’s pathology and cognition are separate objectively measured “facts” which can later be used to create a clinical classification. Any relationship that scientists intimate exists between two or more facts is not a fact but a hypothesis. The coexistence of facts is real and valid and does not need to be questioned unless there is fraud, which is not being suggested. The use of the term “dementia of the Alzheimer’s type” is a factually accurate and objectively determinable observation. It is simply the classification of a person. And it is no different than classifying a car as “blue with bald tires”. We are just stringing objective facts together so that one person can accurately describe something to another person. No reasonable person would assume that the color blue has anything to do with the baldness of tires. Likewise, there is no reason to assume that Alzheimer’s has anything to do with dementia simply because they coexist and are written together in a sentence.
Language is the primary medium that we humans use to communicate with each other. This communication presupposes that we are all using the same dictionary. It does not matter what words we use as long as we have a common understanding of their meaning. Most people associate the term “Alzheimer’s” with the definition of dementia of the Alzheimer’s type described above. I created Lectures 3 (Cognition), 5 (Neurofibrillary Tangles), and 6 (Amyloid Plaques) so that regular people, front-line doctors, and scientists can be given an opportunity to understand each of these phenomena in isolation and with clarity.
The reason why scientists initially assumed that amyloid plaques and neurofibrillary tangles were the underlying cause of cognitive impairment is because that is what they were looking for. They were not looking for the cause of amyloid plaques and neurofibrillary tangles. Therefore, even though reduced cognition, amyloid plaques and neurofibrillary tangles were co-existent facts, it just seems more obvious that these neuropathologies are toxic and somehow causing harm than reduced cognition is toxic and causing neuropathology. It even sounds weird written out. Because the neurotoxicity of these neuropathologies seems so obvious, scientists just cannot believe that it is not true, despite more than 30 years of trying to prove it and failing. As weird as it sounds, the phrase “reduced cognition is neurotoxic”, is true. Technically, reduced acetylcholine neurotransmission, the biochemical system responsible for cognition (as described in Lecture 3 – The Biochemistry of Cognition), is neurotoxic. This is described in detail in Lecture 4 – The Biochemistry and Neuropathology of Impaired Cognition
Part III – Neuropathology is not the cause of reduced cognition
The initial neuropathological studies in persons with late-stage dementia consistently showed widespread amyloid plaque and neurofibrillary tangle neuropathology throughout the cortex. These observations were consistent with the neuropathology is neurotoxic hypothesis even if the mechanism of this toxicity had not been worked out yet. However, as more detailed research was performed on the timing, distribution, and subcellular location of these neuropathologies, it became clear very early on that these pathologies could not be the underlying cause of reduced cognition.
Neurofibrillary tangles are pathological deposits formed from the abnormal phosphorylation of a protein called tau. Tau is a protein that is found in the axons of neurons and its normal function is to assist and accelerate the transport of organelles like mitochondria from the neuron cell body to the axon terminal. Axon terminals are areas of high metabolic activity and is where one neuron projects its signal to a subsequent neuron. Neurofibrillary tangles are found inside neurons. Importantly, they are found in the cell body and dendrites of neurons post-synaptic to cholinergic neurons, not in the axons.
Amyloid plaques are pathological deposits formed from the abnormal (impaired) membrane processing of a protein called amyloid precursor protein (APP). In neurons, APP is a protein whose main purpose is to act as a precursor to a protein fragment called secreted APP-alpha (sAPPα). sAPPα is an axon terminal neurotrophic factor that promotes neurite growth, neurogenesis and neuron survival. When the production of sAPPα is impaired, the over-production of a secondary APP product called Amyloid-Beta 1-42 (Aβ1-42) occurs. Aβ1-42 is the main component of amyloid plaques. Amyloid plaques are found outside neurons. Amyloid plaques are also found in areas around the axon terminals from cholinergic neurons.
The accumulation of amyloid plaque deposits between neurons and neurofibrillary tangles within neurons is not rare. These are commonly observed pathologies in the brain. It is rare to find elderly persons without these pathologies in their brains. In 1997 German neuropathologists Heiko and Eva Braak published a comprehensive analysis on 2661 post-mortem brains from persons aged 25-95 called, “Frequency of Stages of Alzheimer-Related Lesions in Different Age Categories”. Each person was graded as having either no, mild, moderate, or severe deposits of neurofibrillary tangles or amyloid plaques. About 20% of persons under age 40 have mild deposits of neurofibrillary tangles, but less than 1% had mild amyloid plaques. Cases of moderate to severe neurofibrillary tangle density begins at age 66-70 (~10%) and steadily increases to ~60% in persons aged 90-95. Cases of moderate to severe amyloid plaques likewise begin around age 66-70 (~20%) and likewise steadily increase to ~60% in persons aged 91-95. Less than half of persons with moderate to severe Alzheimer’s neuropathology are cognitively impaired.
Earlier, in 1991, these same authors published more detailed neuropathological examinations on 83 post-mortem brains with varying degrees of amyloid and neurofibrillary neuropathology in persons with and without clinical dementia. They observed that the initial deposits of amyloid are found in the basal portions of the isocortex, but that the initial formation of neurofibrillary tangles is in the transentorhinal cortex. These are completely different areas of the brain. Clearly, there is no direct temporal relationship between the two neuropathologies – one does not lead to the other.
Regarding neurofibrillary tangles they state:
“Three kinds of neurofibrillary (NF) changes can be distinguished, i.e. neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NT). NP are marked by a dense feltwork of argyrophilic nerve cell processes. In addition, diffuse amyloid and/or amyloid cores are frequently present within the reaches of such plaques. NFT develop within the nerve cell soma from where they may extend into the dendrites. The proximal axon remains free of such changes. Initial stages of NFT are located in the vicinity of lipofuscin deposits. After deterioration of the parent cell the NFT converts into an extra-neuronal structure (“ghost tangle”) eventually becoming engulfed and degraded by astrocytes. NT consist of argyrophilic processes of nerve cells loosely scattered throughout the neuropil. In the isocortex, they frequently occur in dendrites of tangle bearing pyramidal cells. NT contribute considerably to the total NF changes.”
There is a lot of information in this paragraph! Let me try to translate:
- Argyrophilic nerve cell processes means neuronal processes that accumulate silver stain. Silver staining is a neuropathological technique to identify damaged neurons. Only damaged neurons accumulate silver stain and therefore silver stain is used to visualize damaged neurons under a microscope. NP is the most severe type of NF neuropathology.
- NFTs are phosphorylated tau, one of the key biomarkers of Alzheimer’s disease. Here they are telling us that even though the function of tau is in the axon, the accumulation of the abnormally phosphorylated tau occurs in the cell body (soma) and in the dendrites. This is a key observation in that axons are supported and protected by a myelin sheath which is maintained by oligodendrocytes. The cell body and dendrites (and axon terminals) are not myelinated and are supported by astrocytes. NFTs are the mildest and earliest type of NF neuropathology.
- NFTs first appear in areas with lipofuscin deposits. Lipofuscin deposits are intracellular membrane bound deposits of cellular waste. Cells with lipofuscin deposits are older and weaker. Lipofuscin is like age spots but in neurons instead of on the skin.
- When a neuron containing NFT dies, the NFT does not get degraded by the surrounding astrocytes. It persists as a ghost tangle.
- Neuropils are the most fragile of neuronal processes. They are unmyelinated (unprotected) projections. Silver stained “threads” in the neuropil indicate damaged and weakened neuronal processes and they are co-localized with neurons containing NFT.
When describing the neuropathology of amyloid plaques they state:
“The plaque-like deposits show considerable variations in shape and size. Most of them remain devoid of pathologically changed argyrophilic nerve cell processes and show neither distortions of the neuropil nor accumulations of glial cells. The nerves situated within the deposits appear virtually unchanged. Amyloid deposits, therefore, should not be confused with “neuritic” plaques.”
- The glial cells referred to here are called microglia. Microglial cells are like immune cells. They are active and mobile – moving around your brain looking for damaged cells. When they find a damaged cell, they attack the cell to kill it and clean up the mess and allow room for a new healthy cell to be created. Activated microglia is inflammation. Healthy cells do not attract microglia. The lack of accumulation of glial cells indicates that the neuronal processes in the amyloid plaque are healthy, not damaged.
- The neuropil is the most fragile of neuronal processes. What Braak and Braak are saying here is that most deposits of amyloid are non-toxic to even the most fragile parts of neuron anatomy.
In the discussion, they state:
“Depositions of amyloid are among the first changes seen in the brain. Most of them do not correspond to neuritic plaques”.
“The fact that accumulations of amyloid are frequently found in the cortex of non-demented individuals in the absence of NF changes has led to the assumption that depositions of amyloid precede the development of NF changes. It is therefore important to note that in quite a number of cases one can also recognize a contrasting pattern with cortical NF changes preceding the deposition of amyloid. The existence of amyloid can, thus, not be considered a prerequisite for the development of NF changes. It remains to be elucidated whether there is a relationship at all between amyloid and NF changes.”
Thirty years ago, in 1991, we had clear and unambiguous information that amyloid in the human brain is largely non-toxic and that there is little to no evidence that amyloid plaques are caused by the formation of NFTs or that NFTs are caused by the accumulation of amyloid. Furthermore, NFTs do not even occur in cholinergic neurons. NFTs occur in glutamate projection neurons.
“The transentorhinal Pre-α projection neurons generally are the first nerve cells in the brain to develop NFT and NT.”
These neurons are post-synaptic to the cholinergic projections.
In 2014, Kuchibhotla and colleagues published the results of their research on the neurological effects of phosphorylated tau. Again, it is best to hear it in their own words:
“Here we used awake in vivo two-photon calcium imaging to monitor neuronal function in rTg4510 mice that overexpress a human mutant form of tau (P301L) and develop cortical NFTs by the age of 7-8 mo. Unexpectedly, NFT-bearing neurons in the visual cortex appeared to be completely functionally intact, to be capable of integrating dendritic inputs and effectively encoding orientation and direction selectivity, and to have a stable baseline resting calcium level. These results suggest a reevaluation of the common assumption that insoluble tau aggregates are sufficient to disrupt neuronal function.”
In Lecture 3, I described the biochemical mechanism of cognition and cognitive decline. Reduced cognition is caused by an impairment in the ability of cholinergic neurons to maintain the release of the neurotransmitter acetylcholine. Period. This is clear, unambiguous and unrefuted. Both the isocortex (initial location of amyloid plaques) and the transentorhinal cortex (initial location of NFTs) are innervated by cholinergic axons.
Based upon the above information, it would be logical to investigate what, if any, negative consequences there are to post-synaptic neurons when cholinergic neurotransmission is impaired. It might surprise you to know that such studies have been done – repeatedly. In each study that investigated the effects of impaired cholinergic neurotransmission, scientists observed an elevation in Aβ1-42 and phosphorylated tau, as well as other key features of “Alzheimer’s Disease”. Imagine that!
This is the point in science where unsubstantiated and falsified hypotheses are supposed to die and the data collected used to build a new hypothesis that is consistent with the observations. In the following lectures, I describe in greater detail both the falsity of the “neuropathology is neurotoxic” hypothesis and the true mechanisms behind cognitive impairment and neuropathology with age.
In Lecture 3 – The Biochemistry of Cognition, I explain the relevant research and literature relating to the biochemistry of cognition. In this lecture the obligate requirement of pre-synaptic cholinergic neurons to maintain acetylcholine biosynthesis is presented. Furthermore, I present the mechanisms through which this obligate requirement fails. The primary reason for this failure is reduced levels of plasmalogens in the membranes of the synapse.
In Lecture 4 – The Biochemistry and Neuropathology of Impaired Cognition, I explain what happens when the receiving cell (the post-synaptic neuron) does not receive sufficient acetylcholine stimulation.
In Lecture 5 – The Biochemistry of Neurofibrillary Tangles, I explain the normal function and regulation of Tau and the biochemical circumstances that cause it to become abnormally phosphorylated and turn into neurofibrillary tangles.
In Lecture 6 – The Biochemistry of Amyloid, I explain the normal function and regulation of the amyloid precursor protein (APP) and the biochemical circumstances that cause its metabolism to become dysfunctional and lead to excessive production and accumulation of AB1-42 and ultimately the formation of extracellular amyloid plaques.