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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Alzheimer's disease | 5/12 | https://en.wikipedia.org/wiki/Alzheimer's_disease | reference | science, encyclopedia | 2026-05-05T11:04:11.975566+00:00 | kb-cron |
The gross (macroscopic) appearance of the brain in Alzheimer's disease is variable. In many cases the cortical sulci are widened and the gyri are shrunken, but the degree of cortical atrophy varies. It can sometimes be difficult to discern, particularly in the very elderly. The areas most affected by atrophy are the medial temporal lobe including the hippocampal formation, the amygdala, the frontal lobe and the parietal lobe; the occipital lobe is relatively unaffected by atrophy. The volume of the ventricles increases in parallel with cortical shrinkage. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progress from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults. These macroscopic changes in the brain are not specific to Alzheimer's and can occur in other disorders and to some extent in normal aging. At the microscopic level, the defining histopathologic characteristics of Alzheimer's disease are abundant amyloid plaques and neurofibrillary tangles in certain brain regions. Both of these abnormalities are clearly visible by microscopy, and amyloid imaging. In the early stages of disease, tangles are present mainly in the medial temporal lobe and plaques are present mainly in the neocortex, but as the disease progresses the lesions proliferate throughout much of the brain. Although it was once thought that Alzheimer's disease can occur without neurofibrillary tangles in the neocortex, newer methods have shown that dementia in these cases can be linked to a comorbid condition, often Lewy body disease. Aβ plaques are dense, mostly insoluble deposits of amyloid beta peptide and cellular material outside and around neurons. Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulates inside neurons. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions.
In addition to plaques and tangles, other neuropathological changes contribute to the clinicopathological features of advanced Alzheimer's disease. These include cerebral Aβ-amyloid angiopathy (CAA), inflammation, and the loss of neurons and synapses. The disappearance of neurons and their synapses is a particularly prominent correlate of dementia, although not all cells are affected equally. Selective vulnerability - that is, why certain neurons and synapses are affected, and others spared - is an important unanswered question. In more than half of the cases examined neuropathologically, and especially in very old people, the pathology of Alzheimer's disease is accompanied by lesions that are characteristic of other brain disorders. The most common of these comorbid conditions are vascular disease, Lewy body disease, and TDP-43 proteinopathy. This mixed pathology can complicate both diagnosis and the evaluation of clinical trials, which often target only one of several potential contributors to dementia.
=== Biochemistry ===
==== Amyloid beta (Aβ) ==== Alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded Aβ protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called Aβ. Aβ is a fragment derived from the larger Aβ precursor protein (APP), a transmembrane protein that penetrates the cell's membrane. APP is critical to neuronal growth, survival, and post-injury repair. In Alzheimer's disease, the enzymes gamma secretase and beta secretase act together in a proteolytic process that divides APP into smaller fragments. One of these fragments is Aβ, which misfolds and self-assembles into fibrils; these fibrils form clumps that deposit outside neurons in dense formations known as Aβ plaques. Excitatory neurons are known to be major producers of Aβ that contribute to extracellular plaque deposition.
==== Phosphorylated tau ==== Alzheimer's disease is also considered a tauopathy due to the abnormal aggregation of the tau protein within cells. Every neuron has a cytoskeleton, an internal support structure partly made up of organelles called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. The tau protein stabilises the microtubules when phosphorylated, and it is therefore called a microtubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation. Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles.