Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that gradually impairs cognitive functions, including memory, language, and reasoning. Pathology refers to the specific physical and molecular changes within the brain that form the disease’s underlying basis. These changes begin decades before symptoms become apparent, highlighting the long preclinical stage.
Key Pathological Hallmarks
The brains of individuals with Alzheimer’s disease exhibit two primary pathological hallmarks: amyloid plaques and neurofibrillary tangles. Amyloid plaques are abnormal, extracellular deposits that accumulate between nerve cells. Their main component is beta-amyloid (Aβ) protein, particularly a sticky version called Aβ42, which aggregates into clumps.
Neurofibrillary tangles are abnormal intracellular aggregates found within neurons. They are primarily composed of hyperphosphorylated tau protein, which normally helps stabilize microtubules within the cell. In AD, tau undergoes excessive phosphorylation, causing it to detach from microtubules and form insoluble, twisted filaments that disrupt the neuron’s internal structure. Both plaques and tangles are required for a neuropathological diagnosis of Alzheimer’s disease.
How Brain Changes Occur
The formation of amyloid plaques begins with Amyloid Precursor Protein (APP), embedded in the neuron’s membrane. Normally, APP is cleaved into harmless fragments. However, in AD, abnormal cleavage by beta-secretase and gamma-secretase enzymes produces sticky beta-amyloid peptides, especially Aβ42, which aggregate into amyloid plaques.
Tau pathology involves the hyperphosphorylation of tau protein, which maintains microtubule stability. When tau becomes hyperphosphorylated, it detaches from microtubules, causing them to lose their integrity and collapse. This abnormal tau then aggregates into insoluble neurofibrillary tangles inside neurons, disrupting their ability to transport essential materials. The accumulation of both amyloid plaques and neurofibrillary tangles leads to synaptic dysfunction, impairing communication between brain cells. These disruptions contribute to neuronal damage and death, a hallmark of AD.
Wider Brain Impacts and Consequences
Beyond plaques and tangles, Alzheimer’s disease involves broader pathological changes affecting overall brain function. Chronic neuroinflammation is a prominent feature, involving sustained activation of the brain’s immune cells, microglia and astrocytes. While these cells normally clear waste and protect the brain, their prolonged activation in AD can release harmful substances, contributing to neuronal damage and cell death.
Changes in blood vessels, known as vascular pathology, also play a role. Cerebral amyloid angiopathy (CAA), a common finding, involves beta-amyloid accumulation in brain blood vessel walls, impairing blood flow and contributing to cognitive decline. Additionally, AD is associated with deficiencies in key neurotransmitter systems, such as acetylcholine, involved in memory and learning. The loss of cholinergic neurons in specific brain regions contributes to observed cognitive symptoms.
Widespread neuronal loss and synaptic damage ultimately lead to brain atrophy, where various brain regions shrink. This shrinkage is noticeable in areas like the hippocampus and cerebral cortex, important for memory and higher cognitive functions. Progressive atrophy reflects the damage and death of brain cells as the disease advances.
The Spread of Pathology
Alzheimer’s disease pathology typically progresses through the brain in a characteristic pattern. Tau pathology often begins in the entorhinal cortex, a memory-related region, before spreading to the hippocampus and other cortical areas. Amyloid plaques also spread throughout the brain, though their initial distribution can differ from tau.
The regional progression of pathology correlates with the progressive nature of AD symptoms. Early cognitive changes, like mild memory problems, align with pathology in memory regions. As the disease advances and pathology spreads, more severe cognitive impairments, including language difficulties and impaired judgment, become apparent. Braak staging describes the typical progression of tau pathology, categorizing its spread through different brain regions.