Tau, the Good, the Bad, and the Misunderstood

Good Tau proteins are abundant in the central nervous system and act as stabilizing molecules for cellular structure. Bad Tau proteins occur when they are replicated in a dysfunctional pattern, via a) mutations, b) the inability to bind to microtubules, and c) hyperphosphorylation leading to Paired Helical Filament (PHF). These bad Tau proteins form too quickly causing them to clump together and lead to what is commonly referred to as “Tau-tangles”.

Tau protein expression is known to become dysfunctional from a) high blood glucose levels, b) high glycation rates, c) insulin resistance, d) processes causing oxidative stress in the brain such as excessive exposure to blue light, ischemia, and alcohol consumption. Influences of mitochondrial DNA is also a important factor. Accumulating evidence suggests that the mitochondrial failure, reduced glucose utilization, and deficient energy metabolism occur very early in the course of Tau-opathies.

According to the CTE Center – Boston University the definition of CTE is, “Chronic Traumatic Encephalopathy (CTE) is a progressive degenerative disease of the brain found in people with a history of repetitive brain trauma (often athletes), including symptomatic concussions as well as asymptomatic sub concussive hits to the head.”[3]

There are two defining characteristics of CTE.

  1. Structural deformations caused by a mechanical trauma.
    1. Macroscopic abnormalities in septum pellucidum which would be disproportionate dilation of third ventricle, or signs of previous brain injury.
  2. Abnormal Tau Formation
    1. Abnormal Tau neuronal lesions affecting the neo cortex, predominately in superficial layers 2 and 3 as opposed to layers 3 and 5 in AD.
    2. Abnormal Tau neurofibrillary lesions in the hippocampus, especially in the CA2 and CA4 regions which differ from preferential involvement of CA1 and subiculum in AD.
    3. Abnormal Tau neuronal and astrocytes lesions in sub cortical nuclei including the mammillary bodies and other hypothalamic nuclei.
    4. Tau ammonal reactive lesions in thorny astrocytes located in subpial periventricular and perivascular regions.

In 1928, the symptoms observed from repeated head trauma that occurred in boxing was coined “punch drunk” by Martland.[4] In 1938, it was updated to “Dementia Pugilistica” by Millspaugh.[5] Early dissections from boxers showed significant brain damage to the brain stem and cerebellum. It was associated to the rotational sheer forces that would occur from impacts to the chin.

Today, CTE is diagnosed by a set of criteria examining the brains of Football players. Clearly the types of impacts routinely sustained by boxers and football players would have different patterns of force transmission causing repeated stress in different locations in the brain.

More recently, a team of researchers led by Dr. Ben Falcon who studied the brains of boxers and football players discovered that there is a cardinal difference in tau protein tangles that occur in these athletes compared to other neurogenerative diseases.[6] That discovery has huge implications for how CTE is defined and identified.

The cardinal difference is that CTE filaments have novel protofilament interfaces resulting in different overall morphology. Moreover, a different confirmation of the B-helix region creates a hydrophobic cavity that is absent in tau filaments seen in AD and other neurogenerative tauopathies.

In plain language the tau protein found in these athletes was structurally different then those found in AD and other neurodegenerative diseases. While both diseases’ progression are dependent on epigenetic controls, their origins are different.

According to the Merriam-Webster.com dictionary, the definition of Alzheimer’s Disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks.[7]

Like CTE there are two defining characteristics of AD.

  1. Extra cellular deposits of A-beta peptide around specific brain regions.
    1. Mutations in the A-beta peptide is genetic and recognized as a cause of AD. This familial genetic disposition usually presents as early onset of AD and represents 5% of all cases.
    2. The remaining 95% of AD cases are sporadic rather then familial and have certain risk factors associated with the development of the disease. These include: 1. Type 2 Diabetes 2. Cardiovascular Disease 3. Traumatic Brain Injury and, 4. Stroke.
  2. Abnormal Tau Formations
    1. Tau neuronal lesions affecting the neo cortex, predominately in layers 3 and 5.
    2. Abnormal Tau neurofibrillary lesions in the hippocampus, predominately in the CA1 region and subiculum.

Risk Factor 1 – Type 2 Diabetes

Alterations in glucose levels and abnormally high rates of glycation play a large role in the accumulation and function of Tau. In fact, insulin resistance is so closely correlated with AD, that it is also referred to as Type 3 Diabetes. The Harvard School of Public Health states that diabetes is largely preventable.[8]

Risk Factor 2 – Cardiovascular Disease

A diseased vascular system can cause inflammation in nearly all areas of the body. Cardiovascular Disease affects the circulatory system and is associated with ischemic conditions (lack of oxygen). According to the worlds leading expert on heart disease, Dr. Mark Houston there are over 400 known offending factors to vascular health and physical impacts is one of them.

According to the American Heart Association we could prevent 90% of heart attacks.[9]

Risk Factor 3 – Stroke

Stroke can cause ischemia and contribute to a common pathology with AD in the modification of Tau proteins.

Risk Factor 4 – TBI

Mechanical traumas cause damage to neurons and can create inflammation and ischemic conditions in the brain. Combined, this could lead to neurodegeneration and act as a catalyst for AD through the abnormal formation of Tau protein.

Continue on to Part 3: CTE is Preventable – A Watershed Moment.

Go back to Part 1: Introduction.


[3] “Frequently Asked Questions about CTE”. Boston University Research: CTE Center.
[4] Harrison Stanford Martland, MD (1883-1954), a Register of His Papers, 1905-1954.
[5] JA Millspaugh: Dementia pugilistica . In: US Naval Medicine Bulletin . 35, 1937, S. 297-303.
[6] Falcon, B., Zivanov, J., Zhang, W. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019). https://doi.org/10.1038/s41586-019-1026-5
[7] Merriam-Webster. (n.d.). Alzheimer’s disease. In Merriam-Webster.com dictionary. Retrieved March 3, 2020, from https://www.merriam-webster.com/dictionary/Alzheimer%27s%20disease
[8] Simple Steps to Preventing Diabetes Harvard T.H. Chan School of Public Health.
[9] Mcgill, H. C., Mcmahan, C. A., & Gidding, S. S. (2008). Preventing Heart Disease in the 21st Century. Circulation, 117(9), 1216–1227. doi: 10.1161/circulationaha.107.717033. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.107.717033.