Alzheimer’s Disease (AD) is best conceptualized 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.
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.
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.