Protein May Hold Key to Alzheimer’s Root Cause

Protein May Hold Key to Alzheimer’s Root Cause

New research finds a promising explanation for how beta amyloid spurs Alzheimer’s, while another clinical trial may find a way to prevent the disease.

Specific Protein Might Be Alzheimer’s Root Cause

By Susan E. Matthews, Everyday Health Staff Writer

Thursday, September 19, 2013 — On the heels of an announcement that the National Institutes of Health will invest $45 million in Alzheimer’s research and the release of the World Alzheimer Report 2013, research published today in Science suggests that a specific class of proteins may be responsible for making the protein beta amyloid toxic to the brain, which causes in the onset of the disease.

For years, researchers have struggled to understand the relationship between beta-amyloid and Alzheimer’s disease. While the buildup of beta amyloid plaques were found in the first cases of Alzheimer’s, and in every person who had the disease since, what puzzled researchers is that some people have comparable levels of beta-amyloid in the brain, but do not develop Alzheimer’s, or other negative effects.

Thus, “something else must be present to allow the amyloid to have neurotoxic effect,” said Richard Lipton, MD, professor and vice chair of neurology at Albert Einstein College of Medicine, who was not involved in the study but noted he’s been “looking for years for the other factors.”

“The single best idea I’ve ever seen for that is in this paper,” said Dr. Lipton. If the protein that the researchers have identified has the effect they assume it has on beta-amyloid, blocking that protein may protect people from Alzheimer’s.

Unexpected Protein in the Brain

Researchers from Stanford University built off of previous work they had done on a protein found in mice, PirB. Previously, this protein was thought to only exist in the immune system, where it binds to T-cells, but they realized it also appears in the brain, explained study author Carla Shatz, PhD, professor of neurobiology and biology at Stanford. When the protein was knocked out in mice models, the researchers realized the brain exhibited higher plasticity, which is essentially the opposite of Alzheimer’s disease. The researchers theorized that beta amyloids may be binding to PirB, which made PirB even stronger, and reduced plasticity at an even faster rate, causing the mental decline exhibited in Alzheimer’s disease.

The researchers crossed mice genetically modified to not carry PirB with mice genetically modified to have Alzheimer’s disease, and found that the resulting mice did not develop the disease nor did they exhibit the memory loss that accompanies the disease.

While this protein was only identified in mice, the researchers were able to identify the analogous protein in humans, LilrB2. This protein could be the target of a new drug therapy that could block it, which would hopefully prevent beta-amyloid from becoming toxic in the brain. As for those people who have high levels of beta-amyloid but not Alzheimer’s, Lipton suggested that they may be naturally deficient of LilrB2.

“This receptor is totally unexpected — it’s not even supposed to be in the brain,” said Dr. Shatz. She noted that while there is still work to be done to confirm the connection in humans, this may offer a new drug target.

Preventing Alzheimer’s Before it Starts

This isn’t the only good news about Alzheimer’s. Yesterday, a paper in the journal Neuron explained how new fluorescent scans may be able to track the progression of the disease, something that could help doctors diagnose the disease. Additionally, the NIH announced yesterday that they would throw $45 million in funds behind several new research projects on Alzheimer’s disease — the largest of which is a $33.2 million grant for a research project out of the Banner Alzheimer’s Institute in Phoenix. The project the grant is funding is also trying to understand how beta amyloid causes Alzheimer’s.

The theory the Banner group is working on is that while there are drugs aimed at reducing amyloids in the brain already, treatment isn’t approved to start until after someone has exhibited signs of Alzheimer’s disease.

None of these treatments has been particularly effective, though, Lipton said.

“The brain has a lot of reserves, and it can withstand lots of loss before dementia develops,” explained Lipton. “By the time Alzheimer’s becomes diagnosable, there’s already huge losses of brain cells and disruption of networks. The horse is already out of the barn.”

The researchers behind the Banner projected, headed by Eric Reiman, MD, executive director of Banner Alzheimer’s Institute, realize this. “Some of these treatments might have their most profound effect if they’re started before the onset of symptoms — before the disease has ravaged the brain,” Dr. Reiman said. So the NIH-funded study is recruiting individuals who have a high genetic likelihood of developing Alzheimer’s disease, but who are so young that they haven’t yet. Their Alzheimer’s prevention registry is already looking for people who may want to be part of the trial. The trials will see if given them a therapy to attack amyloids will reduce their chances of developing Alzheimer’s down the line.

“So far, most studies have focused either on people who have it already or on people who have cognitive impairment,” Lipton said. “That’s the real strength of what the banner group is doing — they’re identifying people very, very early.”

The clinical trial will use “all of the best-established brain imaging” so that the researchers can best understand the results of the treatment. While this makes the trial more expensive, Reiman said he is hopeful that if the treatment seems effective, this could lead to a means of preventing the onset of Alzheimer’s disease in the next generation. “We’re extremely grateful to the NIH and feel a responsibility to get this right,” he said.

State of Alzheimer’s Globally

According to the World Alzheimer Report 2013, released today, more and more people are getting the disease, which is placing an inordinate burden on caretakers and increasing health care costs. Currently, the cost of dementia on the world is equal to 1 percent of global GDP, or roughly $600 billion. By 2050, 227 million adults are expected to require a care giver to help them handle the disease.

Because older adults are living longer than they ever have before, more people are living long enough to get the disease (the risk of the disease increases as people age), Lipton said. Alzheimer’s disease research is chronically underfunded, he said.

“If research funding were proportionate to societal disease burden, then the investment on research into dementia prevention and treatment would need to be increased up to tenfold in order to achieve parity with current investment on research into cancer and cardiovascular disease,” said Martin Prince, professor at King’s College London and author of the report.

The report calls for more investment in both fundamental research on prevention and treatment, but also improvements to how people with the disease are cared for.

For Reiman, the report hits on both of Banner’s goals —that of the clinical trial to accelerate a prevention therapy, and another goal to “establish a new standard of care for patients and care givers.” Reiman emphasized that even though his research is currently focused on prevention, he cannot give up on his clinical patients that already have the disease. At his clinic, they attempt to provide comprehensive care not only for the patients, but also for care givers, who receive a brunt of the stress associated with the disease.

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