Pathophysiology of Alzheimer’s Disease

Understanding the underlying mechanisms of Alzheimer’s disease has evolved significantly in recent years, moving from purely clinical and neuropathological definitions to include biomarker-based frameworks.

Amyloid Cascade Hypothesis

The amyloid cascade hypothesis has been a dominant theory in Alzheimer’s disease research for decades. According to this hypothesis, the accumulation of amyloid-β peptide in the brain is the primary influence driving AD pathogenesis, with other aspects of the disease, including tau pathology and neurodegeneration, occurring downstream of this initial insult (Jack et al. 536).

Amyloid-β is produced through the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase enzymes. In Alzheimer’s disease, there is an imbalance between production and clearance of Aβ, leading to its accumulation in the form of soluble oligomers and insoluble plaques. These Aβ aggregates are thought to be neurotoxic, disrupting synaptic function and ultimately leading to neuronal death.

Tau Pathology

Tau is a protein that normally helps stabilize microtubules, which are essential for cellular structure and transport. In Alzheimer’s disease, tau becomes hyperphosphorylated, causing it to detach from microtubules and form neurofibrillary tangles inside neurons. This disrupts the cell’s transport system, leading to synaptic dysfunction and eventually, neuronal death.

The relationship between amyloid and tau pathology is complex. While the amyloid cascade hypothesis posits that amyloid pathology precedes and drives tau pathology, recent research suggests that the relationship may be more nuanced, with tau pathology potentially arising independently in some cases (Jack et al. 538).

Neuroinflammation and Glial Involvement

Increasing evidence suggests that neuroinflammation plays a significant role in Alzheimer’s disease pathogenesis. Microglia, the resident immune cells of the brain, and astrocytes, which support neuronal function, become activated in response to Aβ and tau pathology. While this activation is initially protective, aiming to clear toxic protein aggregates, chronic activation can lead to the release of pro-inflammatory cytokines and reactive oxygen species, contributing to neuronal injury and death (Scheltens et al. 1579).

Vascular Contributions

Vascular factors also contribute significantly to Alzheimer’s disease pathogenesis. Cerebrovascular disease, including microinfarcts and white matter lesions, is common in individuals with Alzheimer’s disease and may synergistically interact with AD pathology to accelerate cognitive decline. Additionally, impaired blood-brain barrier function and reduced cerebral blood flow are increasingly recognized as important contributors to AD pathophysiology (Livingston et al. 415).