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Dementia Causes
Causes
All forms of dementia result from the dysfunction or death of large numbers of neurons in the brain. 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.
Abnormal protein aggregation
Many types of dementia, including Alzheimer's disease, dementia with Lewy bodies, Parkinson's dementia, and frontotemporal dementia, involve the accumulation of naturally-occurring brain proteins into abnormal aggregations. Often, these aggregations occur inside neurons, when they may also be called inclusion bodies. Protein aggregations are visible under a microscope, but they are small enough that not even the most advanced magnetic resonance imaging (MRI) machine can yet visualize them in a living human.
Each neurodegenerative disease is defined by the identity and distribution of the aggregated protein or proteins. Indeed, a "definite" diagnosis of a given neurodegenerative disease, like Alzheimer's disease, can usually be made only when abnormal protein aggregations have been positively identified on an actual bit of brain tissue. The relationship between the protein aggregation observed at autopsy and the particular symptoms and other disease features experienced during life may be variable, depending on the disorder. This is why a neurologist, even after the most thorough clinical evaluation, can offer only a "probable" diagnosis.
The actual connection between protein aggregations and the processes that lead to loss of neuronal connections and cell death is a matter of intense research. Some important discoveries have been made, including the ways in which protein aggregations may exert toxic effects on cells.
However, in at least some cases, protein aggregates may be more of a side effect than a cause of neurodegeneration, and the actual cell death-triggering events remain obscure. Discovering protein aggregations in neurons is like discovering an archeological artifact of a lost civilization; it is a solitary clue to a complex—and not easily reconstructed—reality.
Proteins associated with neurodegenerative diseases
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Beta-amyloid |
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Alpha-synuclein |
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TDP |
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Genetics
Genes clearly play a role in the development of some kinds of dementia. However, in Alzheimer's disease 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.
Familial dementia occurs when a single genetic mutation is enough to cause cognitive decline. Such mutations often travel in families in an autosomal dominant pattern, meaning that roughly 50% of the offspring of an affected parent will get the disease. Autosomal dominant genes most commonly noted in Alzheimer's disease are Presenilin-1 and Presenilin-2.
Usually, everyone who inherits the mutation will get dementia, and the age at onset is typically younger than in sporadic, or non-familial, cases. Familial dementia is always less common than sporadic; nevertheless, for some neurodegenerative categories, like prion disease and frontotemporal dementia, mutations account for a greater proportion of overall cases than in, say, Alzheimer's disease. Many secrets of neurodegenerative diseases were discovered by researchers studying families with rare mutations.
Much more commonly, individuals may inherit genes that influence the risk for dementia without actually causing dementia in and of themselves. These genes are normal variants, not mutations, and not all individuals harboring such genes will ever experience cognitive decline. One such gene is called apolipoprotein E (ApoE); this gene occurs naturally in three varieties: ApoE2, ApoE3, and ApoE4.
As is the case for all genes, each of us inherits one copy of the ApoE gene from mother and one from father. Individuals who inherit ApoE4 from both parents have approximately a ten-fold greater risk of developing Alzheimer's disease than people without any copy of ApoE4. This gene variant seems to encourage amyloid deposition in the brain. By contrast, another version of the ApoE gene, called ApoE2, appears to protect against Alzheimer's disease.
In frontotemporal dementia (FTD), a mutation called C90RF72 was discovered in 2011 as the most common cause of familial FTD and amytrophic lateral sclerosis. The other common genetic causes of FTD include MAPT and Progranulin among others.
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