Alzheimer’s disease is a progressive neurological disorder characterized by a slow decline in thinking, behavioral, and social skills that eventually impairs a person’s ability to live independently. The condition arises from profound changes within the brain that begin silently, often decades before the first symptoms of cognitive impairment appear. Understanding where this process starts is fundamental because the location of the initial damage dictates the first noticeable symptoms and maps the disease’s subsequent course. Research has pinpointed a specific, small region deep within the temporal lobe as the original site of destruction.
Pinpointing the Initial Site of Damage
The first area of the brain to show clear signs of damage in Alzheimer’s disease is the Entorhinal Cortex (EC), a small structure located in the medial temporal lobe. This area serves as the main information gateway between the neocortex—the large, wrinkled outer layer of the brain responsible for complex thought—and the hippocampus. The Entorhinal Cortex is deeply involved in forming new memories, spatial navigation, and the perception of time.
Damage beginning in the Entorhinal Cortex explains why the earliest clinical symptoms involve subtle difficulties with recent memory and orientation. Since the EC is the primary relay station for information headed to the hippocampus, its failure means the hippocampus receives corrupted data, hindering its ability to consolidate new memories. The hippocampus, located immediately adjacent to the EC, is responsible for converting short-term memories into long-term storage, and it is the second region to be significantly affected.
Specifically, the lateral entorhinal cortex (LEC) is believed to be the sub-region where the pathology first takes hold. The LEC primarily processes non-spatial information, such as context and object recognition, before relaying it to the hippocampus. This initial damage results in the classic early presentation of the disease: a person may struggle to recall recent conversations or events, repeat questions, or become easily lost.
The Specific Proteins Driving Early Deterioration
The physical damage to the Entorhinal Cortex and hippocampus is caused by the abnormal accumulation of two proteins: beta-amyloid and Tau. While both are hallmarks of Alzheimer’s disease, Tau pathology is more closely linked to the observed neuronal death in the early stages. Beta-amyloid protein fragments first accumulate outside of neurons, forming sticky clumps known as amyloid plaques.
Amyloid plaques begin to build up many years, sometimes even two decades, before symptoms become apparent. This extracellular accumulation is considered an initiating event in the disease process, though its presence alone does not always correlate with the severity of cognitive decline. The second protein, Tau, is normally found inside neurons where it stabilizes microtubules, which act as the cell’s internal transport system.
In Alzheimer’s disease, Tau becomes abnormally altered through hyperphosphorylation. This alteration causes the Tau protein to detach from the microtubules and aggregate into tangled filaments, known as neurofibrillary tangles, inside the cell body. The formation of these tangles blocks the neuron’s transport system, preventing the movement of essential nutrients and molecules, which ultimately leads to the cell’s death.
The distribution of these neurofibrillary tangles closely tracks the progression of symptoms, starting with the highest density in the Entorhinal Cortex and hippocampus. This suggests that while amyloid may begin accumulating first, the hyperphosphorylated Tau pathology is the primary mechanism driving the initial neuronal dysfunction and subsequent cell loss in these memory centers.
How Alzheimer’s Spreads Through the Brain
The characteristic destruction of Alzheimer’s disease does not remain confined to the memory centers; it follows a predictable, systematic pattern of dissemination throughout the brain. This spread is described using the Braak Staging system, which categorizes the disease’s progression based on the location and extent of Tau neurofibrillary tangles. The earliest stages, Braak Stages I and II, are characterized by tangles limited primarily to the transentorhinal region.
The disease then progresses to Braak Stages III and IV, where the Tau pathology moves into the limbic system, including the hippocampus and parts of the amygdala. This anatomical spread mirrors the progression of symptoms, moving from short-term memory problems to a broader range of cognitive deficits. The spread of the abnormal proteins occurs along functionally connected neural pathways, moving from one interconnected region to the next.
In the later stages, Braak Stages V and VI, the pathology becomes extensive, reaching the neocortical areas of the brain. This systematic spread involves the association cortices, which are responsible for complex functions like language, reasoning, spatial awareness, and executive function. As these areas become affected, the symptoms diversify and worsen, leading to difficulties with communication, disorientation, and impaired judgment.