Sunday, September 4, 2011

Some Scientific Background

These are some facts I found on Familial Early On-set Alzheimer's.  The presenilin 2 gene is what the DeMoe's carry.  

Alzheimer's is the opposite of cancer.
Cancer is runaway cell growth.
Alzheimer's is runaway cell death.
—SANDRA STEINGRABER, Origins of Dementia, Part 2

Alzheimer's disease is classified in two ways: by heritability and by age of onset. Familial AD (FAD) follows a certain inheritance pattern, whereas sporadic AD, according to current research, does not show an inheritance pattern.

Alzheimer's disease is also classified as either early-onset or and late-onset. Early-onset AD occurs in people younger than 65 and is called pre-senile dementia. Late-onset AD, the most common form of the disease, occurs after age 65 and is referred to as senile dementia Alzheimer's type (SDAT). Fortunately, early-onset AD is rare (about 5% to 10% of cases) and affects people between the ages of 30 and 65. It often progresses more rapidly than late-onset AD. Some forms of early-onset AD are inherited.
Research to date indicates that most familial AD has an early onset and that about half of all cases of FAD are known to be caused by mutations (defects) in three genes located on three different chromosomes:

    Mutations in the APP gene on chromosome 21
    Mutations in the presenilin 1 gene on chromosome 14
    Mutations in the presenilin 2 gene on chromosome 1

Everyone inherits two copies of each of these genes—one from each parent. A parent carrying a defective version of one of these genes has a 50-50 chance of transmitting the defective gene to each of his or her children. A single defective version of any one of these three genes will cause early AD nearly 100 percent of the time.
This type of inheritance pattern is called autosomal dominant inheritance. The total known number of these cases is small—between 100 and 200 worldwide. There is no scientific evidence that links these mutations with the more common sporadic, late-onset AD.

Presenilin 1 is a protein found in brain cells. Its function is unknown. However, it may be involved in protein production and trafficking, especially during early development. More than 40 different mutations have been found in the presenilin 1 gene, and these mutations associate with early-onset familial alzheimer's disease. The disease strikes as early as 28 and as late as 62, with an average age of onset in the mid-forties. Mutations in presenilin 1 tend to elevate levels of amyloid beta in the blood, cerebrospinal fluid, and brains of those affected by mutations. Again, mutations in the presenilin 1 gene are dominant. This means that if a mother or father has the mutated presenilin 1 gene that causes alzheimer's disease, then each of their children has a 50-50 chance of having the mutation. Those children with the mutation have an almost virtual certainty of developing the disease.

Nearly 5.2 million Americans are living with Alzheimer's disease; although most of them are older, about 5% have a form of the disease called early-onset Alzheimer's. This condition can be diagnosed in people in their 30s, 40s, and 50s.
Although early-onset Alzheimer's disease is rare, those who suspect that they or a loved one have it should seek the advice of a physician immediately, regardless of age. New medications show promising results in slowing the progression of the disease. And although the diagnosis is certainly scary, a proactive approach is not only practical but can give those affected some sense of control over what lies ahead.

All Alzheimer's disease involves the progressive degeneration of the brain cells, beginning with the hippocampus, the area of the brain that processes memories, and the cerebral cortex, which is responsible for decision making and thought processes. Scientists aren't certain what causes the degeneration or why the progression of the disease varies tremendously among individuals. Most cases of late-onset Alzheimer's disease, usually diagnosed in people over the age of 65, are what researchers call "sporadic" or not necessarily hereditary, although the trigger hasn't been identified. However, researchers agree that almost all early-onset Alzheimer's disease is inherited.

A Strong Genetic Link
Inherited Alzheimer's is also referred to as familial Alzheimer's disease (FAD). According to the National Institute on Aging, if a parent has the familial form of early-onset Alzheimer's disease, his children have a 50% chance of developing the condition.
Mutations on three genes have been linked to familial, early-onset Alzheimer's disease. These genes have been labeled PS1, PS2 and APP by researchers.

Research from the 1990s indicates that mutations on a gene labeled PS1 may be responsible for 30% to 60% of early-onset Alzheimer's cases. Newer research is inconclusive regarding the exact prevalence of specific mutations, but confirms that a PS1 gene is the mutation most commonly linked to FAD.
It is possible to undergo genetic testing for these gene mutations, but there are many pros and cons to doing so, ranging from being able to provide this important health information to your children to coping with the knowledge that Alzheimer's is inevitable. A trusted doctor or genetic counselor can help you decide whether genetic testing is right for you or a loved one. Be sure to check with your insurance company before pursuing testing, because the coverage for costs of testing varies, and some policies don't pay for any of it.

ScienceDaily (June 11, 2010) — Researchers have discovered how mutations in the presenilin 1 gene cause early-onset Alzheimer's disease (AD). The finding, reported online in the journal Cell, opens the door to developing novel treatments for this form of the mind-robbing disease and for the more common, late-onset form that develops later in life and affects millions of people worldwide. 
The presenilin gene is most commonly associated with the early-onset familial form of Alzheimer's, which runs in families and can strike people in their 30s. The gene was discovered 15 years ago, but until now no one understood how mutations in the gene caused the disease.

The researchers led by Ralph Nixon , MD, PhD, professor in the Departments of Psychiatry and Cell Biology at NYU Langone Medical Center and director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research, discovered that the presenilin 1 gene performs a crucial biological function that enables cells to digest unwanted proteins and is essential for brain cell survival. The mutations, they report, disrupt this cellular protein-recycling process, killing nerve cells.

"In mouse models of Alzheimer's disease and in skin cell of patients with Alzheimer's disease caused by presenilin mutations, we observed that the ability to break down and reuse normal proteins and to remove potentially toxic damaged proteins and organelles is severely impaired," says Dr. Nixon who is also director of the Center of Excellence on Brain Aging and the Silberstein Alzheimer's Institute at NYU Langone Medical Center. The impairment can kill nerve cells, and the loss of neurons does not appear to be dependent on amyloid beta, the plaque-forming protein found in the brains of patients.

"Most of the drug development for Alzheimer's has been focused on removing amyloid from the brain," says Dr. Nixon. "Our findings strongly suggest that there are alternative pathways that can be targeted as well. For example, therapies could be aimed at repairing the cellular mechanism that eliminates toxic proteins before they damage the brain."

Preliminary observations from ongoing studies at the Nathan Kline Institute, says Dr. Nixon, indicate that similar disruptions of the cellular protein-recycling process occur in neurons affected by late-onset Alzheimer's, suggesting that factors other than mutations in the presenilin gene can also impair this process.

More than 160 rare mutations in the presenilin 1 gene and two others have been found to cause early-onset familial Alzheimer's disease. Only a few genes associated with late-onset form of Alzheimer's, the most common form of senile dementia, have been identified so far.

"Presently, no effective treatment exists to either slow or prevent the progression of Alzheimer's disease," says Dr. Nixon. "There is urgent need to see Alzheimer's disease as multi-factorial and to approach the treatment from that perspective."

Funding for this research was provided by the National Institutes of Health (NIH) and the Alzheimer's Association. The study was done in collaboration with NYU Langone's Silberstein Alzheimer's Institute and the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research (NY); The Marion Bessin Liver Research Center at Albert Einstein College of Medicine (NY); Osaka University Graduate School of Medicine (Japan); University of Alberta, Edmonton (Canada); and the University of Chicago (Illinois).

Co-authors include Ju-Hyun Lee, Haung Yu, Asok Kumar, Sooyeon Lee, Panaiyur S. Mohan, Corrinne M. Peterhoff and Devin M. Wolfe of NYU Langone Medical Center. Dr. Yu is presently at the Taub Institute, Columbia University.

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