The cause for most Alzheimer's cases is still essentially unknown
[32][33] (except for 1% to 5% of cases where genetic differences have been identified). Several competing
hypotheses exist trying to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the
cholinergic hypothesis,
[34] 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,
[35] leading to generalised neuroinflammation.
[36]
In 1991, the
amyloid hypothesis postulated that amyloid beta (Aβ) deposits are the fundamental cause of the disease.
[37][38] Support for this postulate comes from the location of the gene for the
amyloid beta 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 AD by 40 years of age.
[39][40] Also
APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.
[41] 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.
[42]
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.
[43] Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.
[44] One receptor for Aβ oligomers may be the
prion protein, the same protein that has been linked to
mad cow disease and the related human condition,
Creutzfeldt-Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.
[45]
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by aging-related processes in later life to cause the neuronal withering of Alzheimer's disease.
[46] N-APP, a fragment of APP from the peptide's
N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as
TNFRSF21).
[46] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the aging brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
A 2004 study found that deposition of amyloid plaques does not correlate well with neuron loss.
[47] This observation supports the
tau hypothesis, the idea that
tau protein abnormalities initiate the disease cascade.
[38] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form
neurofibrillary tangles inside nerve cell bodies.
[48] When this occurs, the
microtubules disintegrate, collapsing the neuron's transport system.
[49] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
[50] Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the
apoE gene.
[51]
Another hypothesis asserts that the disease may be caused by age-related
myelin breakdown in the brain. Demyelination leads to axonal transport disruptions, leading to loss of neurons that become stale. Iron released during myelin breakdown is hypothesized to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as amyloid-beta and tau.
[52][53][54]
Oxidative stress and dys-
homeostasis of
biometal (biology) metabolism may be significant in the formation of the pathology.
[55][56]
AD individuals show 70% loss of
locus coeruleus cells that provide
norepinephrine (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous
antiinflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.
[57] It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their
phagocytosis of Aβ.
[57] This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.
[57]