August 23, 2010

Alzheimer’s Disease Signature Seen in Spinal Fluid

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Levels of 2 proteins in cerebrospinal fluid could potentially be used to identify people with Alzheimer's disease before they show clinical symptoms, according to a new study. The finding could open new opportunities for developing Alzheimer’s therapies.

Alzheimer's disease is an irreversible, progressive brain disorder. It starts with mild memory problems and ends with severe brain damage. Symptoms generally appear after age 60, but the disease is thought to begin years, perhaps even decades, earlier. Today doctors can diagnose Alzheimer's disease only after symptoms have become noticeable.

Alzheimer's disease is characterized by brain abnormalities called plaques and tangles. Plaques are clumps of protein fragments called beta-amyloid in the spaces between the brain’s nerve cells. Tangles are masses of twisted tau protein threads found inside nerve cells.

Several lines of research funded by NIH aim to reliably diagnose Alzheimer's disease as early as possible. One promising approach has been to test for the presence of biomarkers, such as beta-amyloid and tau, in cerebrospinal fluid, which is much more accessible than the brain itself. Because of the time lag before Alzheimer’s symptoms appear, it's been difficult for researchers to determine whether this method would be useful for detecting the disease in its earliest stages.

Researchers led by Drs. John Trojanowski and Les Shaw of the University of Pennsylvania set out to further investigate the use of biomarkers in predicting Alzheimer’s disease. Their work was based on data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a collaborative research effort supported by NIH's National Institute on Aging (NIA) and others. The researchers used the ADNI database to compare cerebrospinal fluid biomarkers in more than 100 people diagnosed with Alzheimer's disease, 200 people with mild cognitive impairment and over 100 cognitively normal subjects.

In the August 2010 edition of Archives of Neurology, the scientists explained that 2 biomarkers form a distinct Alzheimer's signature. The signature—reduced levels of a specific beta-amyloid protein and increased levels of a phosphorylated tau protein—was found in 90% of Alzheimer's patients, 72% of people with mild cognitive impairment and 36% of cognitively normal volunteers.

The researchers validated their model in 2 independent studies. They found that the Alzheimer's signature was present in all 57 subjects who had mild cognitive impairment and progressed to Alzheimer's disease over the next 5 years. The signature was also seen in 64 of 68 (94%) Alzheimer’s cases that were confirmed by autopsy.

The presence of the protein signature in more than a third of the cognitively normal subjects suggests that Alzheimer's disease may be active and detectable earlier than researchers had previously thought. The scientists found that the cognitively normal group with the Alzheimer’s signature was enriched in carriers of the apolipoprotein E ε4 gene variant—a well-characterized risk factor for Alzheimer's disease. Nevertheless, the finding will need to be confirmed in studies that follow people for several years.

With further development, this research may one day allow doctors to identify healthy people at risk for Alzheimer’s disease. Knowing who's at risk would enable scientists to test treatments that might slow or prevent the progression of cognitive impairment.

—by Harrison Wein, Ph.D.

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