Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by a decline in memory, thinking, and behavior. This deterioration is driven by specific, identifiable biological and structural changes, or pathology, that occur within the brain. These changes are characterized by the abnormal accumulation of misfolded proteins, which disrupt the fundamental processes allowing brain cells to communicate and survive. Understanding these pathological events provides insight into the complex mechanisms leading to cognitive impairment.
The Aggregation of Amyloid Beta Proteins
The pathological process begins with the mishandling of a normal protein called Amyloid Precursor Protein (APP), which spans the membranes of neurons. For reasons that are not fully understood, this protein is incorrectly cleaved, or cut, by specialized enzymes in the brain. APP is processed by two enzymes, beta-secretase (BACE1) and gamma-secretase, in a sequence known as the amyloidogenic pathway. This sequential cleavage releases a fragment called Amyloid-beta (A \(\beta\)) peptide into the space outside the neurons.
The A \(\beta\) peptide is naturally “sticky,” and the A \(\beta\) 42 form is particularly prone to clumping together. These peptides first aggregate into small, soluble clusters called oligomers, which are considered highly toxic to the brain’s communication system. As the oligomers accumulate, they eventually form larger, insoluble deposits known as amyloid plaques, visible as dense, extracellular lesions between neurons. While plaques are the visible hallmark of the disease, the smaller, soluble oligomers are the primary agents of early synaptic damage and dysfunction.
Hyperphosphorylated Tau and Intracellular Tangles
The second major protein abnormality occurs inside the cell and involves a protein called Tau. The normal function of Tau is to bind to and stabilize structures called microtubules, which act as the internal “railroad tracks” for transporting nutrients, signaling molecules, and organelles throughout the long extensions of the neuron. This transport system is crucial for neuronal health and communication.
In Alzheimer’s disease, Tau undergoes a pathological change called hyperphosphorylation, where an excessive number of phosphate groups attach to the protein. This abnormal modification causes the Tau protein to detach from the microtubules, which then destabilize and collapse, effectively destroying the neuron’s internal transport system. The free Tau proteins misfold and aggregate with one another, forming insoluble clumps known as Neurofibrillary Tangles (NFTs).
These tangles are intracellular lesions that accumulate within the cell body, blocking internal communication and transport necessary for survival. The density of these Neurofibrillary Tangles in the outer layer of the brain, the neocortex, correlates strongly with the severity of dementia and cognitive decline. The collapse of the microtubule network starves the neuron by preventing the delivery of essential materials.
Functional Breakdown of Neural Communication
The combined presence of extracellular amyloid plaques and intracellular neurofibrillary tangles directly sabotages the brain’s communication network. Amyloid-beta oligomers are believed to be the earliest disrupters of synaptic transmission, the process by which neurons pass signals to one another. These oligomers interfere with chemical and electrical signaling at the synapse, impairing the brain’s ability to form and retrieve memories.
The internal damage caused by hyperphosphorylated Tau compounds this dysfunction by destroying the neuron’s structural integrity. The loss of the microtubule transport system prevents the maintenance and repair of synapses, which are the physical sites of memory storage. Widespread synaptic dysfunction leads to the death of the neuron, causing the progressive brain atrophy observed in the disease. The loss of synapses correlates most strongly with the degree of cognitive decline experienced by the patient.
Chronic Neuroinflammation and Disease Progression
The brain’s immune system, composed primarily of specialized cells called microglia and astrocytes, is heavily implicated in the progression of Alzheimer’s disease. In a healthy brain, microglia act as the clean-up crew, actively clearing debris and damaged cells, including Amyloid-beta. However, chronic exposure to accumulating amyloid plaques and neurofibrillary tangles causes these glial cells to become constantly activated and dysfunctional.
This persistent activation shifts the immune response from a protective function to a destructive state of chronic neuroinflammation. Activated microglia and astrocytes release toxic signaling molecules and pro-inflammatory chemicals. This inflammatory environment damages surrounding healthy neurons, accelerating the formation of both plaques and tangles, thus driving the disease forward. Neuroinflammation acts as an accelerating factor, transforming initial protein misfolding into a cycle of widespread neuronal destruction and progressive functional decline.