Alzheimer Disease ll: Pathophysiology

Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.

Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal processing of amyloid precursor protein (APP) leads to the accumulation of Aβ, disrupting communication between neurons and eventually causing their death.

Within neurons, the tau protein, which normally supports the internal structure, becomes chemically altered. It detaches from microtubules, becomes hyperphosphorylated, and forms twisted strands called neurofibrillary tangles. These tangles disrupt intracellular transport and contribute to neuronal death. Although not unique to Alzheimer disease, they are a hallmark of its pathology.

As these abnormalities accumulate, neurons and synapses are progressively lost, especially in areas responsible for memory and thinking, such as the hippocampus, the entorhinal cortex, and the frontal and temporal lobes. The brain shrinks in volume, with widened sulci, thinned gyri, and enlarged ventricles.

In addition to structural damage, there is degeneration of cholinergic neurons in the basal forebrain, leading to a shortage of acetylcholine—a key neurotransmitter for learning and memory. The combined effects of synaptic loss, neurotransmitter depletion, and neural atrophy result in the cognitive and behavioral symptoms seen in Alzheimer disease.