What Causes Dementia?

All forms of dementia result from the death of nerve cells and/or the loss of communication among these cells. The human brain is a very complex and intricate machine and many factors can interfere with its functioning. Researchers have uncovered many of these factors, but they have not yet been able to fit these puzzle pieces together in order to form a complete picture of how dementias develop.

Many types of dementia, including AD, Lewy body dementia, Parkinson’s dementia, and Pick’s disease, are characterized by abnormal structures called inclusions in the brain. Because these inclusions, which contain abnormal proteins, are so common in people with dementia, researchers suspect that they play a role in the development of symptoms. However, that role is unknown, and in some cases the inclusions may simply be a side effect of the disease process that leads to the dementia.

Genes clearly play a role in the development of some kinds of dementia. However, in AD and many other disorders, the dementia usually cannot be tied to a single abnormal gene. Instead, these forms of dementia appear to result from a complex interaction of genes, lifestyle factors, and other environmental influences.

Researchers have identified several genes that influence susceptibility to AD. Mutations in three of the known genes for AD – genes that control the production of proteins such as amyloid precursor protein (APP), presenilin 1, and presenilin 2 - are linked to early-onset forms of the disease.

Variations in another gene, called apolipoprotein E (apoE), have been linked to an increased risk of late-onset AD. The apoE gene does not cause the disease by itself, but one version of the gene, called apoE epsilon4 (apoE E4), appears to increase the risk of AD. People with two copies of the apoE E4 gene have about ten times the risk of developing AD compared to people without apoE E4. This gene variant seems to encourage amyloid deposition in the brain. One study also found that this gene is associated with shorter survival in men with AD. In contrast, another version of the apoE gene, called apoE E2, appears to protect against AD.

Studies have suggested that mutations in another gene, called CYP46, may contribute to an increased risk of developing late-onset sporadic AD. This gene normally produces a protein that helps the brain metabolize cholesterol.

Scientists are trying to determine how beta amyloid influences the development of AD. A number of studies indicate that the buildup of this protein initiates a complex chain of events that culminates in dementia. One study found that beta amyloid buildup in the brain triggers cells called microglia, which act like janitors that mop up potentially harmful substances in the brain, to release a potent neurotoxin called peroxynitrite. This may contribute to nerve cell death in AD. Another study found that beta amyloid causes a protein called p35 to be split into two proteins. One of the resulting proteins triggers changes in the tau protein that lead to formation of neurofibrillary tangles. A third study found that beta amyloid activates cell-death enzymes called caspases that alter the tau protein in a way that causes it to form tangles. Researchers believe these tangles may contribute to the neuron death in AD.

Vascular dementia can be caused by cerebrovascular disease or any other condition that prevents normal blood flow to the brain. Without a normal supply of blood, brain cells cannot obtain the oxygen they need to work correctly, and they often become so deprived that they die.

The causes of other types of dementias vary. Some, such as CJD and GSS, have been tied to abnormal forms of specific proteins. Others, including Huntington’s disease and FTDP-17, have been linked to defects in a single gene. Post-traumatic dementia is directly related to brain cell death after injury. HIV-associated dementia is clearly tied to infection by the HIV virus, although the exact way the virus causes damage is not yet certain. For other dementias, such as corticobasal degeneration and most types of frontotemporal dementia, the underlying causes have not yet been identified.

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