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Changes linked to Alzheimer's disease evident even in young brains

A new study suggests where and when -- though not yet how -- Alzheimer's may begin

Scientists know that Alzheimer’s disease gains a foothold in a patient’s brain years before he or she first stashes car keys in the freezer, or gets lost coming home from the store. But a new study suggests that the changes in the brain that set the stage for Alzheimer’s may start decades -- indeed a lifetime -- before dementia symptoms appear.

The latest research found that people as young as 20 have detectable levels of beta-amyloid molecules -- the building blocks of the amyloid plaques that are a key physical signs of Alzheimer’s -- in a group of brain cells that come under attack in Alzheimer's disease. In older people who were cognitively normal at the time of their death, researchers also found amyloid molecules, usually in greater concentrations and often already clumped together, in those special neurons.

The scientists looked specifically at the cholinergic neurons in the basal forebrain, which are among the first to sustain damage and to die off in Alzheimer's disease. Researchers found that all of the brains they studied tended to accumulate more amyloid molecules -- and more "clumps" of the sticky protein -- inside those cells with age. 

Their findings appear in the journal Brain.

"What this suggests is that Alzheimer's disease is truly a lifelong process," said the study's lead author, Changiz Geula, a neuroscientist with the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University’s Feinberg School of Medicine.

"If we were to try to prevent the formation of clumps in this population, these findings would suggest we would have to intervene when a person is much, much younger," he added.

At very low levels of concentration, amyloid molecules appear to be normal and perhaps even perform some valuable function in the basal forebrain's cholinergic neurons, Geula said in an interview. Over time, their concentration appears to build, and they form clumps called oligomers in those cells.

Nerve cells in other areas of the brain did not show the same extent of amyloid accumulation. The latest research therefore suggests that these neurons are where Alzheimer's disease starts, and that all people appear to have a supply of its building blocks there. For reasons as yet undiscovered, however, some people collect more amyloid in these neurons than others as they age.

In many, these concentrations become so dense that the amyloid sticks or clumps together. For an unlucky few, these clumps become so big and so plentiful that they form tough and insoluble clumps -- plaques. Those plaques begin to appear outside the cells, where they cause neurons to die and disrupt electrical signals among the survivors. Problems with memory and executive function become apparent.

"The exciting idea implied by this report is that the biology that goes awry in Alzheimer's disease ... may be initially manifest in large neurons in this brain region throughout life," said University of Hawaii neurologist and Alzheimer's disease researcher Dr. Lon White, who was not involved in the latest study.

If that's so, White added, researchers should plumb the operations of the basal forebrain's cholinergic neurons in early and middle age to discover what, exactly, sets off the trajectory whereby concentrations of amyloid grow unchecked.

To discern age-related patterns in the concentration of amyloid in the special cells of the forebrain, scientists drew upon Northwestern University's Alzheimer's Disease Brain Bank and from tissue from other brains contributed by pathologists from other institutions.

The researchers analyzed brains from 13 cognitively normal people ages 20 to 66, 14 people ages 70 to 99 who showed no signs of dementia, 21 individuals ages  60 to 91 who had been diagnosed with Alzheimer's, and "super-aged" two women who, at 90 and 95 years old, had performed on memory tests on a par with an average 50- to 65-year-old.

In the cells of the basal forebrain, scientists found that amyloid molecules began accumulating in young adulthood and continued throughout the lifespan. Individuals in their 20s and other normal young individuals showed amyloid and some signs of early clumping. But the clumps in older individuals and those with Alzheimer’s were larger.

White praised researchers for studying the brains of people who died prematurely of other causes in a bid to capture the earliest seeds of Alzheimer's disease.

"In order to understand what goes wrong in the pathogenesis of clinical Alzheimer's disease, we must understand the biochemical and physiologic aspects of amyloid biology not just in old, demented persons who have come to autopsy, but in the normal brain at all ages," he said.

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