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Tracking what triggers onset of Alzheimer's disease

Karen Henley, chief caregiver for her husband, Mike,

Karen Henley, chief caregiver for her husband, Mike, who is disabled with Alzheimer's, measures his medicine at their home in Westbury. (Dec. 4, 2007) Credit: Newsday/J. Conrad Williams Jr.

Critical to understanding Alzheimer's is grasping the complex interplay between genes and the development of the disease.

But here's the problem - and it is one of the toughest in medical science: Even though researchers have found three genes intimately linked to early-onset Alzheimer's, the kind of that occurs before age 65, they have yet to pinpoint the elusive trigger that sets the disease in motion.

Despite the lack of clarity on the precise mechanism triggering an unstoppable cascade of brain-destroying events, scientists are certain of this: If you carry one of the deadly early-onset genes you will definitely develop the Alzheimer's.

"Early-onset disease is very, very rare," said Dr. Philippe Marambaud of the Feinstein Institute for Medical Research in Manhasset, a division of the North Shore-Long Island Jewish Health System. "The majority of cases are late-onset disease."

Working with Dr. Fabien Compagne of Weill Medical College of Cornell University in Manhattan, the two researchers last year discovered a late-onset gene, a stretch of DNA on chromosome 10 known as a risk gene. He and Compagne dubbed it the DNA CALHM1.

Having CALHM1 or any one of the handful of other late-onset genes does not mean you're destined to develop Alzheimer's in old age, just that you're at elevated risk.

Alzheimer's is a tragedy regardless of the age when it appears. The disease purloins memory starting with the facts, figures and faces most recently learned. As it progresses, it guts the history of one's life, even knowledge of oneself. In the 10 to 20 years it takes for the insidious process to completely rout the mind, the person becomes an incontinent, unresponsive empty shell.

DNA-hunters worldwide were able to track down defective early-onset genes by studying families in which the disease had deeply seeded itself throughout the roots and branches of the family tree, haunting members over numerous generations.

Flaws leading to early-onset Alzheimer's can be found on chromosomes 1, 14 or 21. People who possess the defects cannot escape an Alzheimer's fate.

"I like to use the term deterministic because basically it's like this: If you don't get hit by a truck, you will develop Alzheimer's disease," said Dr. Robert Green. A pioneering Alzheimer's epidemiologist at Boston University, Green has studied the psychological impact that comes with being handed a positive test for an early-onset gene.

Yet even though there is a difference between carrying an early or late onset gene there are no differences in the pathology that mars the brain. In either case, the brain is mottled with typifying plaques and tangles, proteins that gradually - insidiously - eat away the mind.

In addition to CALHM1, discovered by Marambaud and Compagne, risk genes for late-onset Alzheimer's are believed to reside on chromosomes 9, 10, 12 and 19. Sweeping searches of the human genome are continuing but the gene-tracking task isn't easy, experts say.

"These are not families where Alzheimer's is predictably occurring," said Dr. Sam Gandy, a professor of medicine at Mount Sinai School of Medicine in Manhattan and past chairman of the Alzheimer's Association's medical and scientific advisory council.

Screenings exists to reveal if a gene for elevated risk is present. Scientists have known for nearly two decades, Gandy added, that APOE-4, a cholesterol-related gene serves as a marker for late-in-life Alzheimer's risk. About 40 percent of all people who develop late-onset Alzheimer's carry the telltale variant, which is present in about a quarter of the U.S population.

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