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Risk Gene for Alzheimer's Disease May Aid Prevention

Researchers have identified the chain reaction that may lead to the disease.

A new study provides a clearer understanding of how the gene Apolipoprotein E4 (ApoE4) affects late, age-dependent Alzheimer's disease (AD). The findings may pave the way for better treatment and prevention, according to the researchers. The study was published in the Journal of Neuroscience, May 13, 2015.

THE VIEW FROM DUKE

SOPHIA WANG, MD, Staff Psychiatrist-Durham VA Medical Center; Asst. Professor of Psychiatry & Behavioral Sciences, Department of Psychiatry-Div. of Psychiatry/Geriatric Behavioral Health, Duke

Novel Treatments to Treat or Prevent AD are Much Needed

"Alzheimer's disease causes progressive, irreversible loss of memory, and affects more than 5 million Americans. Novel treatments which can either treat or prevent Alzheimer's disease are much needed. Apolipoprotein E4 (ApoE4) is a well-established risk factor for late-onset Alzheimer's disease, but it is not well known how ApoE4 may increase the risk for Alzheimer's disease. Recent work now suggests that ApoE4 may increase the risk for Alzheimer's disease by indirectly lowering levels of brain-derived neurotrophic factor (BDNF). BDNF is important for building, repairing, and maintaining the connections between brain cells. The loss of BDNF is thought to be associated with the cognitive deficits seen in Alzheimer's disease. A new drug, bryostatin 1, may work by preventing ApoE4 from decreasing BDNF levels. Bryostatin is currently being tested in small-scale clinical trials to see whether it may benefit patients with Alzheimer's disease. If shown to be effective, bryostatin would be a novel class of drugs to treat this common, devastating disease."

ApoE4 is a major genetic risk factor for a majority of Alzheimer's patients. In fact, people with two copies of the ApoE4 gene are 10 times more likely to suffer from the disease. The link between ApoE4 and Alzheimer's is much like a domino effect: In a recent study, scientists found that the ApoE4 gene increases the activity of histone deacetylases (HDACs) in brain neurons. HDACs are enzymes that act like on/off buttons for genes. In response, this higher activity of HDACs reduces levels of DNA-programmed, brain-derived neurotrophic factor (BDNF).

Essential Synapses.

"BDNF fosters the growth, maintenance, and repair of synapses—the process of how nerve cells signal to other cells," says lead researcher Daniel Alkon, MD, of the Blanchette Rockefeller Neurosciences Institute in Morgantown, W.Va. Synapses are essential for storing memories and processing thoughts and planning."The loss of synapses is the pathologic (disease-causing) change in Alzheimer's that most closely relates to its progressive cognitive deficits."

Previous autopsy studies have shown that many brains of Alzheimer's patients have deficits in BDNF, adds Dr. Alkon. "So we can now see a connection between ApoE4 and lower BDNF and an increased risk of Alzheimer's."

Shift in Treatment Focus.

Current drug therapy for Alzheimer's focuses on reducing the telltale physical signs of the disease—build-up of plaque on the brain caused by the clumping of proteins called beta amyloid, and twisted intracellular tau fibers in brain cells called "tangles." "Yet, so far these drug approaches have been singularly unsuccessful," says Dr. Alkon.

However, the new research could provide a major shift in how to approach treatment. "Synaptic loss can occur before the onset of beta amyloid plaques or tangles, so conventional anti-amyloid and anti-tau approaches are not targeting a critical pathway by which Alzheimer's disease may develop," says Dr. Alkon.

Using this new research as a guide, one way to tackle the disease may be with bryostatin drugs. Pre-clinical studies have found that bryostatins can prevent ApoE4 from hindering BDNF production, and thus stop the chain reaction that may lead to Alzheimer's. Clinical trials with Bryostatin are under way.

"This is a possible next step that could offer a different way to approach Alzheimer's disease treatment and even prevention, especially for people who may be at a higher risk," says Dr. Alkon.

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