What Causes AD? Non-Genetic Factors in AD Development

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Researchers have also investigated a number of avenues related to non-genetic factors involved in AD. Exploration of these factors may suggest new theories about the mechanisms involved in triggering or continuing the disease process.

One promising area relates to a longstanding theory of aging. This theory suggests that the buildup of damage from oxidative processes in neurons causes a loss of function. Scientists believe that particular types of molecules, called free radicals, which are themselves short-lived and produced through normal metabolic mechanisms, play a role in several diseases, including cancer and AD. The body produces free radicals as a by-product of metabolism, and free radicals may help cells in certain ways, such as in fighting infection. However, too many free radicals can injure cells because free radicals are highly reactive and can readily modify other nearby molecules, such as those in the cell membrane or in DNA. The resulting, newly combined molecule can then set off a chain reaction, releasing additional free radicals that can further damage neurons. Oxidative damage due to free radicals may contribute to the development of AD by several means, including upsetting the delicate membrane machinery that regulates the flow of substances in and out of the cell, and altering the structure of certain proteins. Unique characteristics of the brain, including its high rate of metabolism and the long life span of its non-dividing cells, may make it particularly vulnerable to oxidative stress.

Another promising possibility is that inflammation in the brain may play an important role in AD. Brain inflammation increases with age, but it is much more pronounced in AD patients. Investigators have both direct and indirect evidence that inflammation contributes to AD damage. Indirect evidence comes from the fact that in epidemiologic studies and in the NIA’s intramural Baltimore Longitudinal Study of Aging, frequent use of anti-inflammatory agents is correlated with a decreased prevalence of AD (Stewart et al., 1997). More direct evidence comes from the fact that various compounds known to be involved in inflammatory processes can be found in AD plaques, and a number of studies suggest ways in which inflammatory pathways could destroy neurons in an ever-repeating vicious cycle (Griffin et al., 1998). Many scientists are currently conducting studies to understand this process more fully and to explore possible therapeutic approaches that involve anti-inflammatory medications.

In a third area, investigators at the Sanders-Brown Center on Aging and the NIA-supported Alzheimer’s Disease Research Center at the University of Kentucky in Lexington have demonstrated a possible link between brain infarction (stroke) and AD. A brain infarction is an area of injury in brain tissue that usually occurs when the blood supply to that area is interrupted, depriving neurons of essential oxygen and glucose. The researchers have been working with a group of 678 elderly nuns from the School Sisters of Notre Dame who live in convents throughout the United States. In this long-term study of aging and AD, each participating sister agrees to have a yearly physical and cognitive examination and to donate her brain to the study at her death. Results from this ongoing work show that study participants who had had infarctions in certain brain regions had more clinical symptoms of dementia than could be explained by the number of plaques and tangles in their cerebral cortex (Snowdon et al., 1997). These findings suggest that some brain infarcts, which may not themselves be sufficient to cause dementia, may play an important role in increasing the severity of AD’s clinical signs. Other diseases related to the brains’ blood vessels or blood supply, such as atherosclerosis, also may be involved in the development of AD.

Finally, it is becoming clear that there are important parallels between AD and other neurological diseases, including prion diseases, Parkinson’s disease, Huntington’s disease, and fronto-temporal dementia. All involve deposits of abnormal proteins in the brain.

Dr. Stanley Prusiner won the 1997 Nobel Prize in Physiology or Medicine for his discovery of prions, a novel and controversial infectious type of protein. AD and prion diseases, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (“mad cow disease”), cause dementia and death, and both are associated with the formation of insoluble amyloid fibrils, but from membrane proteins that are different from each other. Findings from studying amyloid formation in prion diseases may be useful in studying the similar process in AD.

In 1997, scientists studying Parkinson’s disease, the second most common neurodegenerative disorder after AD, discovered the first gene linked to the disease. This gene codes for a protein called synuclein, which, intriguingly, is also found in the amyloid plaques of AD patients’ brains. Investigators have also discovered that genetic defects in Huntington’s disease, another progressive neurodegenerative disorder that causes dementia, cause the Huntington protein to form into insoluble fibrils very reminiscent of the beta-amyloid fibrils of AD and the protein fibrils of prion disease. Thus, research into each of these neurologic disorders is yielding unexpected insights into the other diseases.


National Institutes of Health

National Institute on Aging


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