Overview

Many researchers prefer to think of druggable targets when evaluating research opportunities. This is logical in many cases where a certain target has been proven to be associated with a disease. But sometimes a disease may be the result of a multifactorial process that may have many potential contributing causes, and that a particular target may only be the most visible manifestation of that process. And maybe not the most important driver of disease.

We hypothesize this may be the case in the search for a treatment for Alzheimer’s disease (AD). Beta-amyloid plaques are the most visible anatomical manifestation of AD, and so beta-amyloid became the drug target of choice. Many monoclonal antibodies capable of removing plaques from the brain were clinically evaluated to see if this that would result in improving cognition or at least slowing down or stopping disease progression. The pursuit of a seemingly obvious druggable target over the past 15+ years has produced 3 products that have received FDA clearance, but many question their clinical utility and widespread market acceptance has not yet been achieved.

Clearly there is room for improvement in therapies for AD. We submit that research at this point should think less in terms of a druggable target and more in terms of a disease process.

We view Alzheimer’s Disease (AD) as a process that plays out over decades resulting in immune activation, chronic neuroinflammation, metabolic dysregulation, the formation of amyloid beta plaques, excessive phosphorylation of tau proteins, disruption of synapse function and eventually neuron death. There is no single cause but rather a complex interaction of factors that are part of the process leading to chronic inflammation in the brain. Chronic inflammation (IL-1b, IL-6, TNF-a) is the essential common pathway leading to synaptic dysfunction, dementia and cell death. We submit that dysregulated immunity which leads to chronic non-productive inflammation should be the target of the next generation of therapies for AD.

Causal factors are upstream of neuroinflammation

Any process predisposing to chronic neuroinflammation can lay claim to being a causal factor. Causal factors interact with one another and are best conceptualized through a systems biology approach utilizing a 3-dimensional network model progressing through time.

We stress the importance of neuroinflammation, insulin resistance and elevated brain cortisol.

The downstream consequences of chronic neuroinflammation result in the metabolic and histologic findings of AD. We view amyloid beta production as a component of innate immune activation and the inflammatory response. Amyloid beta amplifies inflammation in a feed- forward loop. Hyperphosphorylation of tau proteins is part of dysregulated metabolic processes eventually resulting in neuron malfunction and neurodegeneration.

Insulin resistance impairs the brain's ability to use glucose for energy and disrupts insulin signaling, which can lead to the accumulation of beta-amyloid plaques and neurofibrillary tangles. Additionally, insulin resistance can cause inflammation and oxidative stress, which can further contribute to the disease process.

Elevated cortisol is known to damage brain cells and impair memory and cognitive function. Sustained high levels of cortisol can damage the hippocampus and increase the production of beta-amyloid. It also leads to inflammation and oxidative stress, which can contribute to the development and progression of the disease.

Potential Therapies

All AD risk factors involve neuroinflammation. First and foremost, effective therapy must reduce chronic inflammation either by direct anti-inflammatory mechanisms or by removing upstream causal factors — or preferably by doing both.