Alzheimer’s disease is a progressive neurodegenerative disorder that gradually impairs memory, thinking, and behavior, ultimately affecting a person’s ability to perform daily tasks. It is the most common form of dementia, accounting for a significant majority of cases in individuals over 65. Understanding the biological changes in the brain is fundamental to comprehending the disease’s progression. This article explores the underlying brain pathology.
Key Pathological Hallmarks
The defining features of Alzheimer’s disease pathology are the accumulation of two types of abnormal protein deposits in the brain: amyloid plaques and neurofibrillary tangles. These structures interfere with normal brain function and are widespread in affected individuals. The presence of these hallmarks distinguishes Alzheimer’s from other forms of dementia.
Amyloid plaques are dense, extracellular deposits found between nerve cells. They are primarily composed of a protein fragment called beta-amyloid (Aβ). Beta-amyloid is derived from amyloid precursor protein (APP). In Alzheimer’s disease, APP is abnormally cleaved by enzymes, leading to Aβ fragments that aggregate into insoluble clumps.
Neurofibrillary tangles are abnormal bundles of twisted filaments that accumulate inside neurons. These tangles are made of hyperphosphorylated tau protein. Normally, tau stabilizes microtubules, which transport essential substances within neurons. In Alzheimer’s disease, tau becomes excessively phosphorylated, detaching from microtubules and aggregating into insoluble tangles. This disruption compromises the neuron’s internal transport system and can lead to cell death.
Cellular and Synaptic Dysfunction
Amyloid plaques and neurofibrillary tangles disrupt normal neuronal function, leading to cellular stress, inflammation, and widespread neuronal damage. Over time, this results in a significant loss of nerve cells, particularly in regions like the hippocampus and cerebral cortex, which are crucial for memory and cognitive processes.
Synaptic loss and dysfunction are strongly linked to the cognitive decline observed in Alzheimer’s disease. The accumulation of Aβ oligomers—small, soluble aggregates of beta-amyloid—and tau pathology directly impairs the communication points between neurons, called synapses. This impairment means that electrical and chemical signals cannot be effectively transmitted, leading to a breakdown in neural networks. The magnitude of synapse loss correlates more strongly with the severity of dementia than the number of plaques or tangles alone.
The widespread loss of neurons and synapses ultimately leads to observable brain shrinkage, known as atrophy. This atrophy is particularly prominent in areas like the temporal and parietal lobes, as well as parts of the frontal cortex and cingulate gyrus. Brain atrophy can be detected even in the preclinical stages of the disease, and its progression correlates with the spread of tau and amyloid-beta pathologies.
Contributing Factors to Pathological Progression
Other factors contribute to Alzheimer’s disease progression. Neuroinflammation, involving activated immune cells in the brain, plays a substantial role. Microglia and astrocytes, the brain’s resident immune cells, become activated in response to amyloid plaques and tau tangles.
Initially, activated microglia may attempt to clear Aβ, but prolonged activation can lead to a chronic pro-inflammatory state. This sustained inflammation, characterized by the release of pro-inflammatory molecules like interleukin 6 (IL-6) and tumor necrosis factor (TNF-α), can damage neurons and further exacerbate tau accumulation. The interplay between microglia and astrocytes creates a cycle that intensifies neuroinflammation, contributing to neuronal and synaptic dysfunction.
Vascular contributions also influence Alzheimer’s disease progression. Issues with blood vessels in the brain, such as impaired blood flow and dysfunction of the blood-brain barrier (BBB), can worsen the disease. The BBB normally regulates the passage of substances between the bloodstream and the brain. When the BBB is compromised, it can lead to reduced clearance of Aβ from the brain and allow harmful substances from the blood to enter, promoting inflammation and neuronal damage.
Genetic influences also play a part, with certain genes increasing the risk of developing Alzheimer’s disease. The Apolipoprotein E (APOE) gene, particularly the APOEε4 allele, is the strongest genetic risk factor for sporadic Alzheimer’s disease. This allele is associated with increased production and reduced clearance of cerebral amyloid-beta, leading to a higher burden of amyloid plaques. The APOEε4 allele also influences tau pathology, suggesting its role in the complex interplay of factors driving the disease.