The Decades-Long Slide of Alzheimer’s...

Memory loss and personality changes are clear signs of Alzheimer’s, though scientists have become increasingly aware of subtle changes in the brain and body that appear years before the disease is diagnosed. Now researchers have mapped out a sequence of events that precedes overt Alzheimer’s, with some appearing decades before symptoms become obvious.

"A series of changes begins in the brain decades before the symptoms of Alzheimer's disease are noticed by patients or families, and this cascade of events may provide a timeline for symptomatic onset," said lead author Dr. Randall Bateman of Washington University School of Medicine in St. Louis. "As we learn more about the origins of Alzheimer's to plan preventive treatments, this Alzheimer's timeline will be invaluable for successful drug trials."

Scientists hope that treating Alzheimer’s early, before the disease has damaged the brain extensively, may offer the most promise for slowing or halting the disease’s progress, or even preventing it in the first place. Current Alzheimer’s drugs can provide modest benefits for a time, but do not stop the progression of Alzheimer’s.

For the study, published online in the New England Journal of Medicine, researchers closely followed 128 men and women who lived in families that were genetically predisposed to the form of Alzheimer’s that strikes people at a relatively young age. They had a 50 percent chance of inheriting one of the genes that causes early-onset Alzheimer’s.

Even though most people who get Alzheimer’s have the far more common late-onset form which strikes in a person’s 60s, 70s or older, the scientists believe that studying this early-onset group, who tend to get overt Alzheimer’s in their 40s or even younger, will provide vital clues about how the disease progresses.

The study participants, most in their 30s and 40s, were given extensive memory and thinking tests, as well as brain scans and blood and spinal fluid tests to look for markers of Alzheimer’s, over a period of several years. Fifty-one of them carried an early-onset gene for Alzheimer’s (either presenilin 1, presenilin 2, or a gene called APP), which guarantees that they would get the disease.

The researchers also took detailed family histories to determine when parents developed Alzheimer’s. In this group, early-onset disease had been diagnosed among parents around age 45.

From these tests, the researchers ran statistical analyses to estimate when changes signaling Alzheimer’s disease first became evident. They found that in spinal fluid tests, drops in levels of beta-amyloid, a toxic protein linked to Alzheimer’s, occurred up to 25 years before Alzheimer’s was likely to become evident to patients and family members.

They also found that beta-amyloid brain plaques, a hallmark of Alzheimer’s, began to appear up to 15 years before disease became apparent. The researchers are planning follow-up studies to see whether new drugs that are designed to block or remove plaques in the brain, even before symptoms become disabling, may help slow or halt progression of the disease.

The researchers also found that 15 years before Alzheimer’s symptoms became apparent, parts of the brain critical for memory began to shrink. Spinal fluid levels of tau, a protein that forms tangled clumps in the brains of those with Alzheimer’s, also began to rise.

A decade before disease onset, the brain was less able to take up glucose, or blood sugar, an indication of a slowing brain. Those who were destined to get Alzheimer’s also had slight impairments in episodic memory, critical for remembering times, places and other contextual knowledge, though the changes would be too subtle to be recognized by family members or friends.

"These exciting findings are the first to confirm what we have long suspected, that disease onset begins years before the first sign of cognitive decline or memory loss," said Laurie Ryan, clinical trials program director at the National Institute on Aging, which funded the study. "And while [these] participants are at risk for the rare, genetic form of the disease, insights gained from the study will greatly inform our understanding of late-onset Alzheimer's disease."

By ALZinfo.org, The Alzheimer's Information Site. Reviewed by William J. Netzer, Ph.D., Fisher Center for Alzheimer's Research Foundation at The Rockefeller University.

Source: R. J. Bateman, C. Xiong, T.L.S. Benzinger, et. al. Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease. The New England Journal of Medicine, July 11, 2012.

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