Pathology of Alzheimer’s Disease – Cure Alzheimer's Fund

Alzheimer’s disease is a progressive brain disorder that profoundly impacts our memory, induces cognitive impairment and, in the final stages, can lead to physical dysfunction. At first the changes are mild, but they gradually become more and more disruptive to life.

The human brain contains billions of nerve cells, known as neurons, with trillions of connections whose communication with one another is crucial for everything we do, from reading to remembering names to completing daily tasks. In Alzheimer’s disease, this communication is disrupted and impaired. The culprits behind these disruptions that lead to the pathology of Alzheimer’s disease are amyloid beta plaques, formation of neurofibrillary tau tangles and prolonged inflammation in the brain. This underlying pathology may take two or more decades to develop, and the progression can be different for each patient.

Marked by the accumulation of amyloid beta plaques and neurofibrillary tau tangles in the brain, Alzheimer’s disease gradually leads to the death of neurons, resulting in memory loss, impaired thinking and the degradation of the physical structure of the brain. As the disease advances, even the simplest tasks become impossible. Eventually, Alzheimer’s disease leads to death.

Changes in the brain begin to develop decades before symptoms occur. By the time a person has received a diagnosis of Alzheimer’s disease, the brain already has suffered significant irreversible damage. The lengthy preclinical stage before symptoms appear highlights the complexity of Alzheimer’s disease and the challenge in diagnosing and treating it.

THE BASIC PATHOLOGY OF ALZHEIMER’S DISEASE

Amyloid Beta Plaques: Clumps of Protein Between Neurons
The amyloid precursor protein is found in the brain and throughout the body; it has a number of important roles in cellular health and brain function. Amyloid precursor protein is abundant in neurons and has a role in the formation of synapses, which are essential for communication of biological messages between our neurons. With normal brain function, amyloid precursor protein is cleaved into small fragments known as amyloid beta; the brain processes and removes the fragments as waste. However, in Alzheimer’s disease, amyloid beta begins to accumulate as clumps (plaques) between neurons, interfering with neuronal communication and impeding the normal exchange of essential signals between the brain cells. Click here to read more about the dual role of amyloid beta.

Tau Tangles: Twisted Proteins Inside Neurons
Tau is another protein in the brain. Its function is to stabilize the internal structure of nerve cells by supporting the internal scaffolding and signaling transport system of our neurons. In a healthy brain, the tau proteins undergo a normal process called phosphorylation. In Alzheimer’s disease, the tau proteins become overphosphorylated. Rather than provide support, they begin to stick together, forming tangles that block the neuron’s transport system. This blockage prevents nutrients and other essential molecules from moving throughout the neuron, leading to cell death. The spread of tau tangles throughout the brain is closely associated with the progression of Alzheimer’s disease symptoms. Click on this link to read more about tau variants and their impact on the progression of Alzheimer’s disease.

Neuroinflammation: The Body’s Response to Plaques and Tangles
The body has natural methods for removing debris and toxins; the same is true for the brain. In the healthy brain, the microglia—the primary immune cell in the brain—engulf and destroy toxins and other unwanted debris. This response is the activation of the brain’s immune system to injury, disease or infection, and the release of immune cells is designed to protect the brain from further injury. When the accumulating amyloid beta plaques and tau tangles of Alzheimer’s disease trigger the immune response, the brain’s natural waste managers, the microglia, become overactivated and, instead, release harmful substances that cause further damage to the neurons. This process accelerates cell death and further impairs brain function. Use this link to learn more.

The Vicious Cycle
In Alzheimer’s disease, plaques, tangles and neuroinflammation form a harmful cycle. Amyloid beta plaques can disrupt neuron communication and trigger an immune response; tau tangles disrupt the internal workings of neurons, contributing to their death. Neuroinflammation, initially a response to clear plaques and tangles, exacerbates the situation by triggering more plaque and tangle formation by releasing inflammatory molecules. This creates a self-perpetuating cycle where plaques and tangles promote inflammation, and inflammation, in turn, promotes the formation of more plaques and tangles, driving the progression of Alzheimer’s disease and cell death, leading to atrophy of the brain.

In addition to numerous grants focused on the role of amyloid beta in Alzheimer’s disease, Cure Alzheimer’s Fund supports two highly innovative large-scale efforts—consortia—currently focused on tau and neuroimmune responses. Use this link to learn more about these consortia.