TREATMENT & PREVENTION OF NEUROINFLAMMATION in
TBI, HD, PD and AD
Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease are chronic, progressive, and age-related neurodegenerative brain diseases
Neuroinflammation drives brain disease years and even decades before symptoms appear.
There is an age-related chronicity to neurodegenerative disease: Neuroinflammation precedes amyloidosis, tauopathy, and cognitive decline.
Anti-inflammatory drugs administered mid-life will treat and even prevent neuroinflammation.
Alzheimer’s disease remains the most dramatically unmet medical need of our time. One would expect the pharmaceutical industry to step up at this critical moment of dramatic need. Instead, risk-averse pharma companies and their investors seem to have taken a step back. The repeated failures of drug candidates in Alzheimer’s disease clinical trials have cast a pall of doubt around the best known disease hypotheses: the amyloid hypothesis and the tau hypothesis. But, the data from failed clinical trials has been widely misinterpreted due to the fact that some of the most highly touted drug candidates, the ‘therapeutic antibodies’, do not even reach the brain. Antibodies, administered peripherally, generally lack sufficient brain exposure to engage their targets effectively. This general failure of antibody drug candidates is what it is: a failure of antibody drug candidates. No more than that. Amyloid and tau are, of course, significant to Alzheimer’s disease pathology. Importantly, orally administered brain-permeable small molecule drugs will necessarily become the future treatments and preventives of Alzheimer’s disease.
Amyloid vs tau
The amyloid and tau hypotheses have been rivals in academia and pharma for over 30 years. The lingering debate around which is the true driver of Alzheimer’s disease has grown stale. Amyloid vs tau has become like two old men sitting on a park bench arguing over who between them is still the most handsome. Amyloid accumulation and tauopathy are, of course, each centrally important. But, Alzheimer’s disease is a chronic, progressive and, above all else, an age-related disease. The amyloid and tau cascades and the associated over-production and mis-folding of proteins are likely the symptomatic products of a more deeply causative age-related driver of neurodegeneration and Alzheimer’s disease: neuroinflammation.
Age-related increases in inflammation correspond to our increasing vulnerability to disease generally as we age.
Inflammation increases systemically as we age. Pro-inflammatory biomarkers including IL-1, IL-6, TNF, and CRP are indicative of this. Age-related increases in inflammation correspond to our increasing vulnerability to disease generally as we age. Inflammation-associated age-related diseases including diabetes, arthritis, cardiovascular disease, and brain diseases are characteristically chronic and progressive. These diseases, like Alzheimer’s disease, progress for years, sometimes, even for decades, prior to the appearance of symptoms. The clear association of inflammation with aging suggests it to be a driver of age-related disease generally. Pro-inflammatory biomarkers are found to increase with age in the brain and the cerebrospinal fluid. This strongly suggests that a chronic, progressive, and age-related increase in neuroinflammation is the driver behind chronic, progressive, and age-related neurodegeneration and Alzheimer’s disease.
This decades-long process has been referred to recently as immunodementia.
Age-related increases in neuroinflammation likely drive amyloid accumulation, tauopathy, neurodegeneration, cognitive decline, and Alzheimer’s disease. This decades-long process has been referred to recently as immunodementia. The ‘chronicity’ of neuroinflammation and neurodegeneration offers a wide window for treatment and prevention. One might draw an analogy to traumatic brain injury (TBI). A football player who suffers TBI as a teenager exhibits associated symptoms in his 50s and 60s. It would seem that inflammatory brain damage due to TBI could be prevented or, at least, minimized, over that time period. The prevention of chronic, progressive, age-related neuroinflammation over years could delay or prevent the onset of symptoms of TBI and Alzheimer’s disease.
Orally administered brain permeable small molecules are being developed as safe and effective anti-neuroinflammatory agents
Currently, orally administered brain permeable small molecules are being developed as safe and effective anti-neuroinflammatory agents. These are intended to be used alone as preventives or co-administered and co-formulated with cognition enhancers and amyloid- and tau-targeted agents as therapeutic drugs for TBI and Alzheimer’s disease.
Orally bioavailable and blood-brain barrier permeable agents will be effective.
The development of ‘preventives’ of inflammation and neuroinflammation is exceedingly important. But, the clinical testing of a preventive agent presents real challenges. One might imagine that the testing of a preventive drug candidate on hundreds or thousands of healthy subjects in a clinical trial to measure disease prevention might be impractical or impossible. The practical difficulty of testing preventives offers an immense opportunity to the developers of dietary supplements and nutraceuticals. Caveat to the developers of dietary supplements and nutraceuticals to prevent neuroinflammation: orally bioavailable and blood-brain barrier permeable agents will be effective. The polyphenol anti-oxidants including resveratrol, curcumin, and the green tea catechins, are all instantaneously metabolized to their glucuronides and sulfates. They are rapidly cleared and never reach the brain. This is not to say that there is no benefit to red wine, whole turmeric, and green tea…It simply means that we have yet to uncover the beneficial compounds.
