Causes of Alzheimer’s Disease
The Alzheimer’s disease is caused by brain cell death. New cells do not grow to replace the dead ones. Over the course of time the loss of brain cells causes the brain to shrink and the fluid spaces that surround the brain get larger to fill up the space. Scientists do not yet know what causes brain cells to begin dying or why it affects mainly older people.
Early-onset Alzheimer’s is a rare form of the disease that occurs in people aged 30 to 60 and represents a very small percentage of all people who have Alzheimer’s disease. Most cases of early-onset Alzheimer’s are root on genetics – a family history of the disease.
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis. Which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.
The genetic heritability of Alzheimer’s disease (and memory components thereof), based on reviews of twin and family studies, range from 49% to 79%. Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65. This form of the disease is known as early onset familial Alzheimer’s disease. Most of autosomal dominant familial AD can be assign to mutations in one of three genes. Those encoding amyloid precursor protein (APP) and presenilins 1 and 2.
Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of Aβ produced. And may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than Aβ. There exist variants of the APP gene which are protective.
In Alzheimer’s disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Finally, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell’s cytoskeleton which collapses the neuron’s transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21. Together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4). Leading to excess amyloid buildup in the brain. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer’s-like brain pathology with spatial learning deficits.