A Possible Key to Treating Alzheimer's

March 2015

The U.S. Centers for Disease Control and Prevention estimates that 5.3 million Americans currently have Alzheimer's disease, and that number is expected to double by 2050 as the population ages. However, no effective treatments for Alzheimer's currently exist.

The laboratory of Professor Jerold Chun (center) includes (left to right) Yun Yung, Richard Rivera, Benjamin Siddoway and Gwendolyn Kaeser.

Now, a team of scientists at The Scripps Research Institute (TSRI) has found that Alzheimer's patients have brains with significantly more genetic variation than normal brains, including extra copies of a gene linked to the disease. The finding may help scientists pinpoint the mechanism that causes Alzheimer's and develop new treatments.

“Our findings open a new window into the normal and diseased brain by providing the first evidence that DNA variation in individual neurons could be related to brain function and Alzheimer's disease,” said Jerold Chun, senior author of the new study and professor at TSRI's Dorris Neuroscience Center.

Alzheimer's disease is an irreversible brain disease that tends to strike older people. It is progressive – impairing memory, destroying motor skills, and eventually causing death. Scientists still do not know what triggers the majority of Alzheimer's cases, making it difficult to develop a treatment. Some genes have been identified in families; however, 95% of cases are “sporadic,” with no link to a gene or family history of Alzheimer's.

Researchers have long known about disease-related protein accumulations (called amyloid plaques) in the brains of Alzheimer's patients. They've also known that chromosome 21 plays a role in the disease, due to Alzheimer's-like symptoms in people with Down syndrome – which is caused by having three copies of chromosome 21. This chromosome contains the APP gene, which can lead to production of the primary component of the damaging amyloid plaques.

In 2001, Dr. Chun was the first to report that the brain contains many distinct genomes within its cells, causing “genomic mosaicism” – an effect much like the colorful tiles in an artist's mosaic. “When we started, genomic mosaicism in the brain was not recognized,” said Dr. Chun. “But it turns out there is a remarkable range of genomic changes encompassed by DNA content variation in single brain cells.”

In the new study, Dr. Chun and his colleagues set out to analyze the overall DNA content in cells, comparing 32 post-mortem Alzheimer's brains and 21 post-mortem non-diseased brains. Remarkably, the researchers found that more than 90% of sporadic Alzheimer's disease brains displayed hundreds of millions more DNA base-pairs compared with control samples, showing that genomic mosaicism was altered in the Alzheimer's brain. Interestingly, these changes were not found everywhere, but were greatest in a part of the brain involved with complex thought.

Further tests showed that neurons from patients with sporadic Alzheimer's disease were four times as likely to contain more than the normal two copies of APP, with some Alzheimer's neurons containing up to 12 copies of APP, a phenomenon never seen in the controls.

While genetic tests on blood samples can reveal if a person is prone to developing an inherited form of Alzheimer's, most people who develop Alzheimer's do not test positive. The new study suggests that such genetic signatures might be lacking in the blood of the majority of patients because the genomic signatures of sporadic Alzheimer's disease occur within individual brain cells.

Indeed, a majority of major brain diseases are also sporadic, and Dr. Chun believes genomic mosaicism could possibly have a role in other brain diseases. Future studies in the Chun lab will investigate the relationship between mosaicism and disease, the causes of mosaicism, and potential new drug targets present in the millions of extra base-pairs found in single Alzheimer's disease neurons.

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