Errant enzyme may cause AD plaque

A faulty molecule may be responsible for the progression of mild cognitive impairment to Alzheimer's disease, according to researchers from Mount Sinai School of Medicine in New York City.

A major effort is under way to find imaging biomarkers that will lead to earlier diagnosis of AD. One such promising marker is β-amyloid plaque, which is associated with AD. Researchers debate, however, whether the plaques cause AD or are a byproduct of the disease.

The Mount Sinai study, which appeared June 10 online in the journal Neurobiology of Aging, suggests the former.

People with AD exhibit elevated levels of β-amyloid peptides that cause plaque buildup in the brain. In the earliest stages of AD, the peptides proliferate, especially in the two connected brain regions critical for memory functions: the hippocampus and entorhinal cortex.

Dr. Giulio M. Pasinetti, director of the Neuroinflammation Research Center, and colleagues theorized that the early increase of β-amyloid peptides could be due to the shutoff in the brains of people at high-risk for developing AD of an insulin-degrading enzyme (IDE) that breaks down the peptides.

To assess possible changes in IDE during MCI, the investigators measured protein levels and enzymatic activity in postmortem brain tissue from 46 elderly subjects. They found that levels of β-amyloid peptides in the entorhinal cortex were inversely correlated with IDE activity in the hippocampus. These results support the idea that alterations in IDE might be causally related to β-amyloid peptide accumulation, starting in the earliest stages of AD, Pasinetti said.

If these results are confirmed, researchers suggest that boosting IDE activity pharmacologically may reverse β-amyloid peptide accumulation.

A loss of IDE activity had previously been shown to occur in severe AD dementia. The current results raise the possibility that a deficit in degradation of amyloid peptides from IDE could raise levels of toxic β-amyloid peptides even before AD dementia is diagnosed.

"We hope our research provides direction for preventive treatments to delay the onset of AD dementia by eliminating amyloid plaque-causing peptides in the brain," Pasinetti said.

For more information from the Diagnostic Imaging archives:

PET/CT imaging distinguishes potentially treatable dementias

Neuroimaging sharpens focus on mild cognitive impairment

Study taps cerebrospinal fluid to identify dementia

Study links Alzheimer's disease to abnormal cell division