nav arrow

Science Behind CogWellin™

There has been no drug approved by the FDA to prevent, slow, or stop the progression of Alzheimer's disease. It is Dr. Ross's position that the wrong target has been engaged and thus the reason for all failures.

CogWellin™ targets the right patients at the right time.

The largest number of Alzheimer's disease trials in the world are targeting amyloid, known as a-beta 1-42. This peptide is a normally-produced protein fragment resulting from the enzymatic cleavage of the amyloid precursor protein (APP), also a normal physiologically important transmembrane protein of uncertain function in mankind. Big and small pharmaceutical have been spending billions of dollars hoping their agents reduce brain levels of a-beta 1-42 in the brain of Alzheimer's disease patients and will result in clinically and statistically meaningful outcomes. By using vaccinations, passive immunizations with monoclonal antibodies, and beta amyloid cleavage enzyme inhibitors (BACE inhibitors), it is hoped a positive outcome will be achieved. All have failed and are highly likely to fail if used alone or used at all. Studies actually administering monoclonal antibodies are now being done on completely asymptomatic individuals who have a scan of the brain that shows amyloid buildup by PET amyloid scanning. Since 35% of adults ages 80 and above have amyloid and they are completely asymptomatic with no data to show which of those 35% will progress into Mild Cogntive Impairment, let alone AD dementia, it too is highly likely to fail. It may also cause a host of unacceptable adverse events such as vasogenic edema of the brain as well as micro and macrohemorrages. These are risks that the FDA has felt acceptable and thus such a study known as the A4 study is well underway.

The most recent targeted protein in the brains of Alzheimer's disease patients is called tubular associated protein, or the acronym TAU. Tau comes in several "flavors" also known as post-translationally modified types. It can be phosphorylated (p-Tau for short), glycosylated, nitrosylated, and even acetylated (see below). Attention by the pharmaceutical industry now has focused on ways to lower p-Tau.

History of CogWellin™ and Salicylates

Since the days of Hippocrates, arguably one of the greatest ancient physicians, the willow bark extract was used for analgesia, anti-inflammation and reduction of fevers.

Native Americans often used this same approach. In the early 19th century, a chemist from Germany, Johann Andreas Buchner, first isolated what was to be eventually known as salicylic acid. He extracted it from the bark of the white willow tree (hence CogWellin LLC's logo, a willow tree embedded in a human brain). Buchner called this chemical "salicin" which is the Latin name for the white willow tree. There are actually two active ingredients of this willow bark: acetylsalicylic acid (commonly known as one of the world's most used non-prescription pill, Aspirin). Aspirin, chemically known as acetyl-salicylic acid, is metabolized in the body into its very active ingredient known as salicylic acid.

Over 75 years ago, the pharmaceutical industry discovered that by combining two molecules of salicylic acid by a simple chemical bond, called an "ester" bond, salsalate was born.

As a practicing geriatrician, Dr. Ross and many thousands of other physicians prescribed salsalate to patients to relieve pain, reduce fever and inflammation. The benefits were quite observable in such patients, but it was noted that a significant percentage of such patients were developing hearing loss and tinnitus (noises in the ear). It was discovered that these side effects were due to high levels of salicylate in the blood and brain. Clearly, the risks of salsalate when administered by prescription in two or three daily doses were not outweighed by its benefits. As newer anti-inflammatory agents such as ibuprofen, naproxen, indomethacin, celecoxib, etc. became available, physicians including Dr. Ross stopped prescribing it to patients.

In Sept 2015, when the seminal article by Min and Gan from Gladstone Institute in San Francisco appeared, their reported use of salsalate in animal models of Alzheimer's disease resulted in dramatic benefits, including reduction in brain atrophy, improved cognitive function, reduction in phospho-Tau and the highly toxic acetylated Tau (Ac-Tau).

It occurred to Dr. Ross that a long-lasting, once-daily salsalate could be the holy grail to finally answer the puzzling question of how to best prevent and treat Alzheimer's disease.

On December 15, 2015, a provisional patent for once daily, long acting salsalate capsule was issued by the US Patent Office. Not only does CogWellin LLC believe this once-daily long-acting salsalate capsule can be useful in slowing progression of Alzheimer's disease, as well as possibly delay the onset of Alzheimer's disease in asymptomatic subjects, it may have a role to reduce the frequency and severity of chronic traumatic encephalopathly (CTE) as well as the many other Tau-associated neuropathies such as progressive supranuclear palsy (PSP), corticobasilar degeneration (CBD), and other neurodegenerative processes.

Because once-daily, long-acting salsalate will deliver safe and hopefully quite effective blood and brain levels of salicylic acid to the "needy neurons", CogWellin™ should be the first FDA-approved drug for treatment and prevention of Alzheimer's disease, with hopefully an acceptable safety profile.

cogwellin history

Lowering Tau

All human beings of all ages have measurable amount of p-Tau in their brains as well as spinal fluid suggesting p-Tau has a normal physiological function. Many studies have shown that at autopsy, nearly all Alzheimer's disease patients have elevated levels of p-Tau. In the cerebrospinal fluid (CSF) of a cognitively normal subject, a normal level of CSF p-Tau can be 25 pg/ml. A level of 90 pg/ml is highly suggestive of a neurodegenerative process as seen in Alzheimer's disease patents. Some of these patients can have normal p-Tau, yet still have Alzheimer's disease by other tests such as PET FDG, or PET amyloid.

So what can one make of the attempts at lowering p-Tau in Alzhimer's disease subjects? If the risks of such treatments with agents that reduce phosphorylation such as kinase inhibitors do not outweigh theoretical benefits, then perhaps the FDA will not deny big pharmaceutical this opportunity. Dr. Ross does not see lowering p-Tau will help, as it is a normal physiologically produced post-translationally modified version of Tau, and perhaps is overproduced due to the pathologically post translationally modified acetylated Tau (Ac-Tau).

cogwellin lowering tau

Acetylated Tau

One must reach deep into the life of an Alzheimer's neuron to understand what could be the earliest and "druggable" target, which Dr. Ross believes is a form of post translationally modified tubular associated unit (TAU) called "acetylated Tau". In Alzheimer's disease, it is Dr. Ross's position that there is an overexpression and overactivity of the enzyme p-300, a well known acetyltransferase. P-300, like all enzymes in the human body, serves a physiological function to simply transfer an acetyl group onto a protein to help normal enzymatic activity.

In Alzheimer's disease, however, the overexpression of p-300 leads to an acetylation of normally non acetylated lysine residues on at least four of the 23 potential lysine residues on the 441 amino acid human Tau protein.

To date, acetylation of lysine residues at K-174, K-274, k-280, and k-281 have been reported in transgenic mouse Tau models as well as in post mortem human Alzheimer's disease brain samples.

Since acetylated Tau has not been found in any significant amount in age matched controls, it appears Ac-Tau should be most certainly thought of as a possible cause, if not strong risk factor, for Alzheimer's disease symptomatology, pathology, and death.

In the now-seminal article by Min and Gan, et al., which appeared in Nature Medicine Sept 21, 2015, the ancient chemical called salicylic acid (the major metabolite of the well known and formerly very well prescribed anti-inflammatory, anti-rheumatic drug salsalate) reduced significantly the level of Ac-Tau in transgenic AD Tau mice, reduced levels of p-Tau, reversed cognitive losses and slowed brain shrinkage.

Salsalate was very familiar to Dr. Ross as a very commonly prescribed medication to ease pain in his geriatric practice. Due to a high incidence of tinnitus (noises in the ear) and hearing loss, it was basically abandoned in favor of other agents such as ibuprofen, celebrex, naproxen, et al. Dr. Ross thought a long-acting version of salsalate would have fewer side effects, can be given once daily, and be the remedy for acetylated Tau and the death it might cause in all Alzheimer's disease patients.

He raced to get a patent on a long acting version of salsalate as soon as that article appeared. On December 15, 2015 the US Patent Office issued Dr. Ross and CogWellin LLC a provisional patent for a once daily formulation of Salsalate. CogWellin™ was born!

poisonous tau

No poisonous Ac-Tau = healthy neurons = healthy brain