Alzheimer Disease ll: Pathophysiology

Neuritic plaques are extracellular deposits that form in the cerebral cortex and around blood vessels. They result from abnormal processing of amyloid precursor protein, leading to accumulation of beta-amyloid, a toxic peptide that aggregates outside neurons. Each plaque has a dense core surrounded by damaged neuronal extensions, astrocytes, and microglia, disrupting synaptic communication and causing neuronal damage.

Neurofibrillary tangles form when tau protein, which normally stabilizes microtubules, becomes hyperphosphorylated and detaches from them. These twisted strands accumulate inside neurons, disrupting intracellular transport and promoting neuronal death. As tangles accumulate throughout the brain, they contribute to progressive neuronal degeneration and cognitive decline.

The hippocampus, entorhinal cortex, and frontal and temporal lobes experience the most significant neuronal and synaptic degeneration in Alzheimer disease. These regions are responsible for memory and thinking, and their progressive loss leads to brain atrophy, including widened sulci, thinned gyri, and enlarged ventricles. This structural damage correlates with the cognitive symptoms observed in patients.

Degeneration of cholinergic neurons in the basal forebrain reduces acetylcholine levels, a key neurotransmitter for learning and memory. This neurotransmitter depletion, combined with synaptic loss and neural atrophy, contributes significantly to the cognitive and behavioral symptoms characteristic of Alzheimer disease. The loss of cholinergic function directly impairs memory formation and retention.

Beta-amyloid is a toxic peptide fragment that results from abnormal processing of amyloid precursor protein. It aggregates extracellularly to form dense-core plaques surrounded by dystrophic neurites, astrocytes, and microglia. These plaques disrupt synaptic communication between neurons and eventually cause their death, leading to progressive cognitive decline.

As Alzheimer disease progresses, neurons and synapses degenerate, causing overall brain atrophy. The brain exhibits widened sulci, thinned gyri, and enlarged ventricles. These structural changes result from the combined effects of neuritic plaques, neurofibrillary tangles, synaptic loss, and cholinergic neuron degeneration, ultimately leading to increased intracranial pressure and further neurological complications.

Amyloid precursor protein undergoes abnormal processing, generating beta-amyloid that accumulates extracellularly in neuritic plaques. Tau protein normally stabilizes microtubules but becomes hyperphosphorylated in Alzheimer disease, detaching from microtubules and forming intracellular neurofibrillary tangles. Both pathological processes disrupt neuronal function and promote cell death through distinct mechanisms.