Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia, a term for a general decline in mental ability. There are many factors that may cause Alzheimer’s disease. These are summarized below.
Alzheimer’s disease and beta-amyloid
Healthy brains are made up of tens of billions of neurons — nerve cells that connect different regions of the brain and send information to and from the brain to the rest of the body. In Alzheimer’s disease, these connections are disrupted by bundles of misfolded proteins called beta-amyloid. Beta-amyloid is formed by the breakdown of larger protein molecules, but instead of being cleared (as in a normal brain) these proteins build up to abnormal levels, causing a toxic effect. As the beta-amyloid proteins find each other, they aggregate or clump, forming plaques.
Alzheimer’s disease and neurofibrillary tangles
Neurofibrillary tangles are abnormal accumulations of a protein called tau that collects inside nerve cells. Healthy nerve cells are supported internally by structures called microtubules, which help guide nutrients and molecules from the cell body to the axon and dendrites (the long extensions of the nerve cells). In healthy neurons, tau proteins bind to microtubules and stabilize them. In Alzheimer’s disease, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside nerve cells. These tangles block the nerve cells’ transport system, damaging them and preventing communication between them.
Alzheimer’s disease and inflammation
Chronic inflammation also may play a role in the development of Alzheimer’s disease. A special type of immune cells present in the brain called microglia are normally involved in clearing the brain of debris and cellular waste. In Alzheimer’s disease, microglia fail to clear away waste, debris, and proteins, including beta-amyloid plaques. Researchers are trying to find out why microglia fail to perform this vital function in Alzheimer’s disease.
Alzheimer’s disease and vascular problems
Changes in the blood vessels that provide the brain with nutrients also are thought to contribute to Alzheimer’s disease. Hardening of the arteries (atherosclerosis) and ministrokes (when blood flow is cut off to a region of the brain) also may cause damage that leads to or accelerates plaque formation. Moreover, the amyloid plaques themselves may cause blockage of blood vessels or cause ruptures of small blood vessels, leading to increased damage and inflammation in the brain.
Alzheimer’s disease and genetics
Genetics is thought to be a key factor in the development of Alzheimer’s disease. A number of genes have been identified that may be linked to the development of the disease, These include APP, PSEN1, PSEN2, and TREM2.
APP, or amyloid precursor protein, is thought to play a role in the normal communication between nerve cells. APP is cleaved by enzymes to produce beta-amyloid. While beta-amyloid may have normal function in the brain, its accumulation and clumping contribute to the formation of amyloid plaques. Mutations in the gene encoding for APP have been linked to the development of Alzheimer’s disease.
PSEN1 encodes for a protein called presenilin 1, which is part of a larger enzyme complex that cleaves to APP. Mutations in PSEN1 are responsible for up to 70% of early-onset Alzheimer’s disease cases. These mutations make the enzyme more active so that toxic beta-amyloid is produced more quickly.
PSEN2 encodes for another enzyme, presenilin 2, which also is responsible for cleaving APP. Mutations in PSEN2 disrupt the function of the enzyme leading to more toxic beta-amyloid being produced.
TREM2 encodes for a protein that tells the microglia cells to clear beta-amyloid plaques from the brain and helps fight inflammation. Mutations in TREM2 cause the microglia not to do their job properly, allowing the buildup of amyloid plaques in the brain. Immune cells gather around the nerve cells and signal to increase chronic inflammation, further damaging them.
Alzheimer’s disease and environmental factors
Many risk factors have been linked to Alzheimer’s disease, although it is unlikely that any one of such factors can cause the disease on its own.
For example, high cholesterol and blood pressure both increase the risk of stroke and atherosclerosis, as do diabetes and obesity. Poor physical health may contribute to the kind of mini-strokes that have been linked to Alzheimer’s disease.
People who smoke have a 45% higher risk of developing Alzheimer’s disease compared to non-smokers, possibly due to increases in inflammation and changes in vascular health. Evidence suggests that people who stop smoking can reduce their risk of developing Alzheimer’s disease.
Head injuries also may increase the risk of developing Alzheimer’s disease, as areas of brain damage have increased swelling and inflammation.
Alzheimer’s disease and aging
The brain changes over the lifetime of an individual, typically shrinking slightly with age (atrophy). While in healthy aging brains there is very little shrinkage; in Alzheimer’s disease there is widespread loss of nerve cells. It is unclear how normal aging differs from the early stages of Alzheimer’s disease, and it is likely that disease arises from a complex series of brain changes that occur over decades.
Last updated: May 31, 2019
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