The deposition of an abnormal protein (amyloid beta) outside nerve cells in the form of amyloid. These are called diffuse plaques and amyloid also forms the core of more organized plaques called senile or neuritic plaques. Recently evidence has begun to accumulate implicating simpler, soluble forms of amyloid (oligomers) in the pathological process, and the presence of plaque amyloid does not correlate well with the degree of dementia. Amyloid also accumulates in the walls of small blood vessels in the brain. This is termed amyloid angiopathy (also called congophilic angiopathy). Another pathological feature of AD is the accumulation of abnormal protein filaments inside nerve cells in the brain, formed from aggregation of tau protein, which is normally present to stabilise microtubules. In AD, an abnormally phosphorylated form of tau protein accumulates as paired helical filaments. Tau accumulates in various forms:
As masses of filaments inside nerve cell body termed neurofibrillary tangles
Inside nerve cell processes in the brain termed neuropil threads
Inside nerve cell processes that surround amyloid plaques - termed dystrophic neurites or plaque neurites.
General non-specific findings include:

Diffuse neuropathology, nerve cells, their processes, and synapses are lost from key brain regions. This results in atrophy of the affected areas and enlargement of the ventricles.
Loss of synaptic contacts between neurons may be related to disruption of axonal transport and to the dysregulation of cell adhesion proteins by presenilins. The presenilins have been identified as part of the processing pathways that produce the amyloid beta protein.
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Neurochemistry
The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated.

Disease Mechanism

Three major competing hypotheses exist to explain the cause of the disease.

The oldest hypothesis is the "cholinergic hypothesis". It states that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.

The other two hypotheses each have their advocates, and have often been described (lightheartedly) as the "tau-ist" and "ba-ptist" viewpoints in scientific publications by Alzheimer's disease researchers. "Tau-ists" believe that the tau protein abnormalities come first and lead to a full disease cascade. "bA-ptists" believe that beta amyloid deposits are the causative factor in the disease. For example, the presence of the APP gene on chromosome 21 is believed to explain the high incidence of early-onset AD pathology in patients with Down syndrome, who carry three copies of chromosome 21 and thus APP itself. The "ba-ptist" theory is finding new supporters due to recent discoveries of impaired vascular and cerebrospinal fluid transport of beta amyloid out of the brain tissues, resulting in a greater risk for plaque formation. A third protein, alpha synuclein, which has already been shown to be important in Parkinson's disease, has also been demonstrated to be associated with amyloid plaques in AD.

The presence of plaques and tangles, however, does not always correlate perfectly with clinical Alzheimer's; in other words, not all people who have plaques and/or tangles manifest symptoms of the disease. Loss of synapses correlates much better with the decline of cognition than the presence of plaques and tangles. Some recent research is focusing on the possibility that plaques and tangles arise as a defense against another, as yet undiscovered, process or substance that itself causes the disease. Researchers are intrigued by the idea that the plaques and tangles might not be the problem, but rather a symptom of the problem. The plaques and neurofibrillary tangles might be doing an adequate job of "containing" the disease until they simply are overwhelmed.