MARKER FOR FAMILIAL ALZHEIMER'S DISEASE DETECTABLE YEARS BEFORE SYMPTOMS APPEAR

Study yields opportunity to test therapies before onset of earliest clinical symptoms

JULY 25, 2005

WORCESTER, Mass. Investigators from the  Department of Neurology at the University of Massachusetts Medical School (UMMS), together with colleagues from the University of Toronto, have discovered that levels of a protein called amyloid β-peptide 42 (Aβ42) in spinal fluid, a known marker for Alzheimer's disease, are abnormally low at least four to 12 years before the expected onset of symptoms in a group of subjects with a particular type of gene mutation that gives them an almost 100% risk of developing the early-onset familial form of the disease. The new study, "Familial Alzheimer disease: Decreases in CSF Aβ42 levels precede cognitive decline," appears in the July 25 issue of Neurology, the journal of the American Academy of Neurology.

Researchers have previously determined that the earliest detectable signs of the brain pathology in Alzheimer's patients are deposits of amyloids such as Aβ42, which may interfere with normal brain function. The most common early-onset familial form of the disease is caused by an inherited mutation in a gene identified as PS1, which increases the level of Aβ42 in the brain, with a concurrent decrease in the level in the spinal fluid. While such purely genetic cases of Alzheimer's disease comprise perhaps five per cent of the total number of cases, the expectation is that treatments for this form of the disease will eventually apply to all forms as well. This new finding provides a window of opportunity for researchers to investigate the impact of therapies in the years before such high-risk individuals might develop symptoms of the disease.

The study was designed and conducted by Majaz Moonis, MD, associate professor of neurology, and Daniel A. Pollen, MD, professor of neurology, at the University of Massachusetts Medical School. "We were surprised to find the same low levels of Aβ42, seen in individuals with advanced disease, in people many years younger than the age at which they could expect symptoms to appear," notes Dr. Moonis. "This finding should lead to numerous clinical trials to identify interventions which will correct abnormalities in the metabolism of Aβ42 long before symptoms would otherwise occur, potentially delaying the onset of symptoms and improving the length and quality of life for individuals faced with early-onset familial Alzheimer's."

Data was obtained from twelve subjects between the ages of 34 and 45, six with the PS1 gene mutation, and a control group of six with normal levels of Aβ42 and no family history of Alzheimer's. "Although the number of subjects with PS1 mutations is small, the differences in the Aβ42 values in the two groups was so great that a very high level of significance was reached," wrote the study authors. Further, with many families afflicted by familial Alzheimer's, the implications of these findings for potential treatments are far-reaching.

While further study with larger groups are needed, Moonis et. al. conclude that, "In these subjects, there is a window of opportunity estimated as at least four to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in Aβ42  metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur. There is no reason to delay using this decline in Aβ42 in spinal fluid as an accessible marker to assess potential disease-modifying treatments before the development of cognitive decline."

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