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Investigators reported that about 35-40 percent of people with Down syndrome in the study who showed declining amyloid beta 42, and declining amyloid beta 42/40 ratios, developed Alzheimer disease over a mean follow-up period of 4.1 years.
In adults with Down syndrome, levels of amyloid beta (Abeta) in plasma provide biomarkers that correlate with the onset of Alzheimer disease (AD), according to a Nov. 2 paper in Neurology, but one biomarker also may correlate with the accelerated aging characteristic of the genetic disorder. That finding could provide a clue to the association between AD and the aging process.
The paper found that about 35 to 40 percent of people with Down syndrome in the study who showed declining Abeta 42, and declining Abeta 42/40 ratios, developed AD over a mean follow-up period of 4.1 years.
Abeta 40, produced in abundance in the brain when enzymes cleave amyloid precursor protein (APP), presumably plays a vital role in the healthy brain. With age, however, Abeta 40 levels rise, and some brains start to produce Abeta 42, a slightly longer peptide widely believed to be toxic to neurons. A 2003 paper in the Archives of Neurology reported that increases in Abeta 40 and 42 correlated with age but not with a diagnosis of mild cognitive impairment (MCI) or AD.
Since then, however, researchers have found that Abeta 42 rises early in the disease process, and then falls, presumably because the brain sequesters the soluble form of Abeta 42 into the insoluble plaques characteristic of AD.
The Neurology paper found evidence of that trend in adults with Down syndrome, who almost always develop AD by their fifth or sixth decade, presumably because they carry a duplication of chromosome 21, which includes the gene for APP. This duplication results in the over-production of APP throughout life, with the cleavage products eventually overwhelming the brain's capacity to clear them. Primitive plaques have been found in infants with Down syndrome, and by puberty amorphous brain plaques are commonplace. However, people with Down syndrome who carry only a partial duplication of chromosome 21 may not produce excess Abeta, and remain free of dementia.
DR. NICOLE SCHUPF: “Clearly what's driving the development of cognitive decline in people with Down syndrome is amyloid beta. They have such elevated levels. We've found that declining Abeta 42, or declining Abeta 42/40 ratios, are very sensitive to the onset of dementia.”
The four-year study involved 225 adults with Down syndrome, and reaffirms findings published by the authors in 2007 in the Archives of Neurology, which demonstrated a reliable correlation between high plasma levels of Abeta 42, and the development of AD. In the current study, 164 of the 225 participants did not develop dementia, while 61 did, and those whose levels of Abeta 42 decreased during the follow-up period were 5 times as likely to develop AD (hazard ratio = 4.9).
“Clearly what's driving the development of cognitive decline in people with Down syndrome is amyloid beta,” said lead author Nicole Schupf, PhD, DrPH, of the Taub Institute for Research on Alzheimer's Disease and Related Disorders. “They have such elevated levels. We've found that declining Abeta 42, or declining Abeta 42/40 ratios, are very sensitive to the onset of dementia.”
CSF levels of beta amyloid and tau 181, and total tau, are still more reliable as biomarkers for AD or mild cognitive impairment (MCI), Dr. Schupf said, “but from a public health perspective you would like a blood test as a screening device rather than a lumbar puncture. Our work has been to find blood biomarkers of risk that can identify people early so if there are ever treatments, you'd know who is at risk.”
Both blood and CSF biomarkers do not always correlate perfectly with the onset of disease symptoms, however, possibly because the disease develops over many years. As a result, by the time Abeta 42 levels are measured, the brain may already have started to aggregate the peptide into insoluble plaques.
“Levels of Abeta 42, and Abeta 42/40 ratios, may already be low in people with MCI, so they would look like healthy elderly,” said Dr. Schupf. “In our work, we've gone back four years, and I'm not sure that's far enough. If the pathological processes that result in Alzheimer disease start 10 years before the onset of symptoms, you have to start then and do serial measures to detect the changes indicative of high risk.”
“There may be autoantibodies to beta amyloid that are clearing this, for example,” said Dr. Schupf, “or there may be differences in the formation of oligomeric forms of Abeta that we don't understand. We've identified clear biomarkers for risk, but not on an individual level.”
“I think this is a terrific paper, very exciting,” said Elizabeth Head, PhD, an associate professor of molecular and biomedical pharmacology at the University of Kentucky's Sanders-Brown Center on Aging, who was not involved with the study. “To see that Abeta 42 went down in plasma is nice and consistent with other papers, but the thing I found so interesting was this increase in Abeta 40. That was quite counterintuitive, but it may suggest that rising levels of Abeta 40 reflect an accelerated aging process, while changes in Abeta 42 reflect a disease process.”
“The observations are interesting and somewhat surprising,” said William C. Mobley, MD, PhD, chair of the Department of Neurosciences at the University of California-San Diego, and an expert on the neurobiology of Down syndrome. “The decline in the ratio of Abeta 42 to Abeta 40 in those with dementia was expected, but the decline reflected a small drop – or no change – in Abeta 42. Rather, the ratio changed primarily because of an increase in Abeta 40. Such changes may distinguish these subjects from those with typical Alzheimer's, and might be telling us something about differences in pathogenesis. The work is important, and the authors should be congratulated.”
While the Neurology paper affirms the correlation between Abeta biomarkers and AD, the looseness of the correlation – in people with Down syndrome as well as in the general population – suggests the influence of some other process, possibly related to aging itself.
DR. WILLIAM C. MOBLEY: ”The decline in the ratio of Abeta 42 to Abeta 40 in those with dementia was expected, but the decline reflected a small drop – or no change – in Abeta 42. Rather, the ratio changed primarily because of an increase in Abeta 40. Such changes may distinguish these subjects from those with typical Alzheimer's, and might be telling us something about differences in pathogenesis. The work is important, and the authors should be congratulated.”
“I think there's probably another event that tips the scale toward dementia,” said Ira T. Lott, MD, professor of pediatrics and neurology at the University of California-Irvine, and chief of neurology at Children's Hospital of Orange County. “We have patients in their mid- to late 60s who have never become demented. Others who are high functioning develop dementia and their course is terminal in three years.”
Dr. Lott has received an NIH grant to identify factors that predict cognitive decline in adults with Down syndrome. “At baseline we will look for potential biomarkers using advanced EEG, PIB imaging, measures of CSF beta and tau levels, cytokine profiling, and mitochondrial studies of oxidative stress,” he said. “We will follow these patients over four years with neuropsychological testing, and we hope to build a predictive model.”