Alzheimer's disease: Encyclopedia II - Alzheimer's disease - Pathology

Alzheimer's disease - Pathology

Alzheimer's disease - Microscopy

There are several changes found in the brain in AD (in order of appearance):

• 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.

Alzheimer's disease - Neurochemistry

The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated.

Alzheimer's disease - 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.

There is compelling evidence that genetic predisposition underlies the development of Alzheimer's disease. However, the most obviously genetic cases are also the rarest. Most cases identified are "sporadic" with no clear family history. It is probable that environmental factors have to interact with a genetic susceptibility to cause development of disease. Head injury has been consistently shown to be linked to later development of AD in epidemiological studies. In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. The most commonly accepted explanation for this last feature is that larger brains simply may have more cells that can afford to be lost. Inheritance of the epsilon 4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Intriguing work is currently going on investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the inflammatory 5-lipoxygenase gene [1].

Studies have not shown strong link with toxins, vitamins, metals or diet, although rabbits fed a high-cholesterol diet in the presence of copper ions in their water did develop amyloid brain lesions and cognitive deficiencies [2], [3]. Likewise, linkage has been found between zinc or copper and reactive oxidative stress contributing to Alzheimer's pathology [4], and the amyloid precursor protein has been shown to alter expression in response to metal supplementation and chelation [5], [6], [7]. Therefore, it is hasty and premature to dismiss any and all environmental effects out of hand. There have been studies that link aluminium to the progression of Alzheimer's, but the results from these studies have not been confirmed and are not widely accepted by Alzheimer's experts.

Rare cases are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial AD (FAD). Evidence from rodent studies suggests that the FAD mutation of PS1 results in impared hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus (Wang et al, 2004). Mutations in the APP gene on chromosome 21 can also cause early onset disease.

Alzheimer's disease - Genetic linkage

Alzheimer's disease is linked to the 1st, 14th, 9th, 19th, and/or 21st chromosomes. While some genes predisposing to AD have been identified, most cases are sporadic. However, sporadic AD most often involves some form of genetic susceptibility.

Adapted from the Wikipedia article "Pathology", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki