The biological causes of Alzheimer's disease are not fully understood and research continues to examine factors involved in the development of Alzheimer's disease. The information below explains some of our current knowledge about the causes of Alzheimer's disease.
> The Role of Plaques and Tangles
> The Genetics of Alzheimer's disease
> Research Theories
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The role of Plaques and Tangles
The two most common hallmarks of Alzheimer's disease in the brain are beta-amyloid plaques and tangles. The role of plaques and tangles in Alzheimer's disease is not fully understood. Both are present in the brains of older people who do not have Alzheimer's disease, although they are more widespread and predominant in the brains of people with Alzheimer's disease. Research is attempting to determine more about the role of both plaques and tangles in the development of Alzheimer's disease.
Plaques are formed from deposits of amyloid-beta protein, as well as a variety of other substances such as other proteins and dead cells. Plaques are dense, sticky and insoluble aggregates that form between and around brain cells. The primary component amyloid-beta protein is formed from abnormal processing of the larger protein Amyloid Precursor Protein (APP), which appears to be important in the growth and survival of brain cells. APP is cut into smaller pieces by specialised enzymes and sometimes one of the fragments is the amyloid-beta protein. In Alzheimer's disease, sticky amyloid-beta fragments clump together and form the basis of plaques.
The role of amyloid-beta in Alzheimer's disease has not been clearly established and it is not completely understood whether it is primarily a cause or an effect of the disease. Researchers continue to study many aspects of amyloid-beta to establish its role in Alzheimer's disease, including the mechanisms of plaque formation, and how plaques might be removed from the brain.
The second common sign of Alzheimer's disease in the brain are called neurofibrillary tangles. These tangles are formed from twisted tau fibres inside brain cells. Tau is a protein which normally helps to maintain the structure of brain cells by strengthening the internal scaffolding of the cell (known as microtubules). In the brain cells of people with Alzheimer's disease, tau proteins don't function properly and instead form protein tangles inside the cell. This leads to a breakdown in the brain cell's ability to communicate with other brain cells and eventually to cell death.
Research has revealed that the tau protein is also damaged in several other neurodegenerative conditions such as frontotemporal dementia and Pick’s disease, indicating that tau may have a wider role in neurodegeneration. Future research will examine the role of the tau tangles in the initial development in Alzheimer’s disease and the association between tau tangles and amyloid-beta plaques.
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The genetics of Alzheimer's disease
Genes and inheritance
Genes are the building instructions for the body and carry the genetic code. Genes are found in every cell in the body in packages of twisted DNA called chromosomes. Half of these chromosomes are inherited from each parent - providing the basis for genetic inheritance. Genes explain why family resemblances occur and why some diseases can run in families.
Genes carry patterns for the many proteins that form our bodies. Proteins are the essential building blocks of life - forming cells, organs, and enzymes which help the body to function. Once they are made, proteins can be folded into different structures and shapes to fulfill their many functions. One example of a protein is keratin, the protein that forms our hair and nails.
There is still much we don't know about the role of genes in Alzheimer's disease and researchers continue to study Alzheimer's disease genetics. In most cases, Alzheimer's disease occurs sporadically, is not directly caused by a gene and has no clear pattern of family inheritance. However, in a minority of cases, Alzheimer's disease can be directly caused by a gene mutation.
Younger onset Alzheimer's disease
Younger onset Alzheimer's disease has a clear pattern of family inheritance and is very rare - accounting for only 5 - 10 % of all cases of Alzheimer's disease. Symptoms usually begin before the age of 65 in the 30s, 40s, or 50s. There are currently three genes that have been linked to younger onset Alzheimer's disease, but it is likely that more genes will be identified.
The three genes linked to younger onset Alzheimer's disease are Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and Amyloid Precursor Protein (APP) genes. In people who develop younger onset Alzheimer's disease, one of these genes is sometimes damaged or mutated. The damaged forms of these genes act to influence protein processing in the brain.
A mutation in the APP gene causes an abnormal type of APP protein to be formed, which is more likely to produce the amyloid-beta plaques that accumulate in the brain in Alzheimer's disease.
The exact function of the presenilin genes PSEN1 and PSEN2 are not known. Some studies have indicated that the presenilin genes might code for specialised enzymes which cut APP into different protein fragments including beta-amyloid protein. Damage to this enzyme (through the gene mutation) could change the way APP is cut and favour the production of amyloid-beta.
Although younger onset Alzheimer's disease represents only a small fraction of the total cases of Alzheimer's disease, insights from research into the genes linked to younger onset Alzheimer's disease has yielded much knowledge about the causes of Alzheimer's disease in general.
Genetic risk factors
In most cases, Alzheimer's disease is not directly caused by a gene mutation. The majority of people with Alzheimer's disease develop Alzheimer's disease after the age of 65, and there is no clear cause. However, researchers have identified a gene that may increase the risk of developing Alzheimer's disease, but does not cause Alzheimer's disease.
Everyone has two copies of the apolipoprotein E (ApoE) gene, which codes for a protein involved in cholesterol transport. There are three common variants of the ApoE gene - E2, E3, and E4. The most common ApoE variant is the E3 type, which does not affect the risk of developing Alzheimer's disease. However, people who carry the E4 subtype have an increased risk of developing Alzheimer's disease.
It is important to note that having the ApoE E4 gene type does not mean you will develop Alzheimer's disease. Many people who have the ApoE4 gene do not develop Alzheimer's disease and many people who do have Alzheimer's disease do not have the ApoE4 gene variant. Many studies are underway to find more genes which may influence the development of Alzheimer's disease.
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Research theories
Research continues to search for causes of Alzheimer's disease. Much research is focused on the roles of amyloid-beta and tau proteins in the development of Alzheimer's disease. However, there are a range of other research avenues examining potential facors in the development of Alzheimer's disease.
Cholinergic hypothesis
The cholinergic hypothesis of Alzheimer's disease is based on studies showing that people with Alzheimer's disease have a reduced level of acetylcholine in their brains. Acetylcholine is a neurotransmitter - a specialised brain chemical that transmits messages between brain cells - that is important in learning, memory and attention. Most of the currently available drug treatments for Alzheimer's disease are based on the cholinergic hypothesis and act to increase levels of acetylcholine in the brain. Current research in this area focuses on determining the role of acetylcholine deficits in Alzheimer's disease, as well as developing more effective acetylcholine based treatments.
Vascular factors
Vascular dementia is the second most common type of dementia, and may account for 15 - 20% all cases of dementia. Vascular dementia can be associated with vascular or circulatory problems in the brain and can often coexist with Alzheimer's disease. Much research is focusing on vascular dementia as well as the role of vascular factors in conjunction with Alzheimer’s disease pathology. Recent findings concerning the overlap between risk factors for vascular disease and Alzheimer's disease, such as high blood pressure, diabetes and high cholesterol levels, have indicated that there may be a strong connection between the development of Alzheimer’s disease and vascular conditions. These findings may have important implications for preventative strategies, suggesting that reducing vascular risk factors could be beneficial for Alzheimer’s disease as well. Research continues to examine the vascular aspect of Alzheimer's disease.
Inflammation
Inflammation is part of the immune system response to fight off damage from disease or injury. However, there is some evidence that excessive inflammation could contribute to Alzheimer's disease. Some evidence suggests that amyloid-beta plaques attract immune cells, leading to a build up of inflammatory factors at the site of plaques, but it is not known whether this is beneficial or harmful.
Several studies have found that anti-inflammatory drugs might lower the risk of developing Alzheimer's disease. However, trials of non-steroidal anti-inflammatory drugs (NSAIDs) in people with Alzheimer's disease have not been very successful and NSAIDs are associated with some serious side effects. Research continues to explore the involvement of inflammation in Alzheimer's disease.
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Cause Links
> Plaques and Tangles
> Genetic factors
> Research Theories
Plaques and Tangles
Alzheimer’s Brain Changes
Information about plaques and tangles from the Alzheimer’s Society of Canada
Plaques and Tangles
Explaining the hallmarks of Alzheimer’s disease by the National Institute on Aging (US)
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Genetic Factors
For more information please see Genes and Genetic Testing section
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Research Theories
The search for causes
Information about research into the causes of Alzheimer’s disease by the National Institute on Aging (US)
For more information see Explaining Research section
