Alzheimer's disease
Our Approach
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 driven by IL-1b, IL-6 and 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.
Pro-Inflammatory cytokines may be what drives the pathology of AD
Pro-inflammatory cytokines significantly influence the progression of AD by contributing to neuroinflammation and neuronal damage. IL-1β, IL-6, and TNF-α are elevated in AD and are associated with several pathological processes:
1. Microglial Activation: These cytokines activate microglia, leading to a chronic inflammatory state that exacerbates amyloid-beta (Aβ) deposition and tau pathology.
2. Neuronal Damage: Pro-inflammatory cytokines promote synaptic dysfunction, neuronal apoptosis, and cognitive decline by influencing pathways involved in neurodegeneration.
3. Feedback Loop: The interaction between Aβ and cytokines creates a feedback loop that perpetuates inflammation and accelerates disease progression. Additionally, increased IL-6 levels correlate with cognitive impairments and reduced hippocampal volume, linking inflammation directly to memory dysfunction. Overall, these cytokines play a crucial role in the pathogenesis and cognitive decline associated with AD.
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.