Alzheimer’s Disease is society’s next big challenge

CAF founders (from left) Henry McCance, Phyllis Rappaport, Jacqui and Jeffrey Morby.
Photo courtesy of curealzfund.org

CAF founders (from left) Henry McCance, Phyllis Rappaport, Jacqui and Jeffrey Morby.

There are currently 5.4 million victims of Alzheimer’s Disease (AD) in the United States. Costing more than the wars in Afghanistan and Iraq combined, AD care takes almost 40 percent of the annual Medicare and Medicaid budget now, and the cost is rising exponentially. Half of all persons over 85 have some form of AD. If a cure is not found, an inflection point or tipping point will be reached in the years between 2015 and 2020, and AD will bankrupt the US health care system, according to the Cure Alzheimer’s Fund (CAF) and the Rotary Club of Martha’s Vineyard. There is as yet no cure.

On Monday evening this week, about 100 concerned citizens, most of them seniors, heard Jeffrey Morby, a co-founder of the CAF, and Harvard professor Rudolph Tanzi PhD, director of genetics and aging research at Mass General Hospital, discuss the prospects for a cure for AD.

Dr. Tanzi reported that for the first time this year in a poll, AD earned the title of “most dreaded” disease. Slowly, often over several years, the patients lose the ability to remember how to do even the simplest activities, recognize friends and loved ones, or even understand what is going on around them. Patients in advanced stages require round-the-clock supervision and help with daily activities. For the 12.9 million family members, the human toll is enormous: not only dollars, but stress, loss of caregivers’ own health, and the heartbreak of “the long goodbye.”

Dr. Tanzi described AD as a “learning disease, not a memory disease.” The brain, he said, is made up of hundreds of millions of neurons, joined with each other by hundreds of trillions, perhaps quadrillions, of synapses. The loss of a few synapses or connections is not at all crucial, as the brain has redundancy built in — a memory is stored in several places, and every time an event is repeated, it is stored again in new places. Moreover, the brain may even have the ability to regenerate synapses. However, we remember something by relating it to something we already know. If enough synapses are destroyed, the brain cannot connect a new experience to what it already knows. Loss of connectivity is a disaster. The short-term memory loss typical of AD is not because the brain can’t remember things, but because it can’t connect things to what it already knows. It’s not that the patient can’t remember where she put her car keys, she never knew where they were, because she couldn’t learn where she put them when she put them down. When told that this unfamiliar woman is his wife, an AD victim can’t connect her to the rest of his life and therefore doesn’t remember what he’s just been told about her.

A quick Alzheimer’s primer

Dr. Tanzi said that what happens in AD is quite well understood from post-mortem examinations of AD and non-AD brains, amyloid imaging techniques, and tests of spinal fluid. What is as yet not well understood is why it happens and, more important, what can be done to stop it. The first event is always an excessive accumulation of amyloid beta-protein peptides (Abeta) in the brain. Amyloids are normal in the brain and part of the way the brain protects itself from disease or trauma. Something causes too much Abeta to accumulate — perhaps a genetic mutation, perhaps a head trauma or stroke, perhaps something as simple as excessive emotional stress. Somehow too much Abeta causes inflammation and triggers the clumping of another protein, Tau, which produces toxic tangles inside the nerve cells of the brain. It is these “tangles” which disrupt the synapses between neurons and causes AD symptoms. However, mysteriously sometimes post-mortem examinations of non-AD patients reveal the presence of tangles, but the person had no dementia. There may be something that protects such people from the disruption of connectivity.

Dr. Tanzi compared an AD patient’s brain to an overflowing sink. The sink overflows because too much water (Abeta) comes in, or because the drain is clogged and not enough water (Abeta) flows out. Research tried to find what causes build-up of Abeta, what drains it away, or what protects people who have too much. CAF is helping to fund studies of the genes that produce or help to produce Abeta (the water faucet) and the genes that remove Abeta from the brain (the drain). Perhaps there is a gene or combination of genes that protects the brain from loss of connectivity even if the sink is overflowing. The problem is that there are about 100 genes involved in the process from Abeta to Tau to tangles. Most them have other functions as well, and eliminating or modifying a gene may cause tremendous harm in other ways. Moreover, brain cells are almost isolated from the body’s blood supply, such that only about two percent of an injected drug reaches brain cells.

Finding a cure

The best hope for curing AD will be to find a way to prevent the build-up of Abeta (too much water in the sink). Finding a cure will be hard, as the recent failure of a promising new drug shows. Pfizer and Johnson & Johnson have been testing bapineuzumab (Bapi), which was theorized to work by interfering with amyloid beta-proteins. Dr. Tanzi commented that Bapi research was very promising, but he was critical of the drug company’s testing. Perhaps not enough of the drug found its way into the brain to work. Perhaps the drug was not Abeta-specific enough. Big drug companies (‘pharma”) do not always make the best partners with researchers in producing drugs, he said. He is encouraged that the National Institutes of Health (NIH) has recently invested seven million dollars in a particular piece of AD research suggested by CAF-funded research. “NIH can be [academics'] new pharma partner,” he said.

CAF has made significant contributions to the search for a cure, beginning with the Alzheimer’s Genome Project in 2005, headed by Dr. Tanzi. Since its conclusion in 2008, researchers can consult a database of over 100 genes associated in some way with AD. That work on the genome continues. CAF also funds a score of other projects that may shed light on AD, funded from $50,000 to $600,000 each. Projects include studies of head trauma, stem cells, type-2 diabetes, Abeta, amyloid pathology, neurogenesis, and various experimental drugs.

The CAF was founded in 2004 by Phyllis and Jerry Rappaport, Henry McCance, and Jeffrey and Jacqui Morby, the hosts for the gathering at Farm Neck. The founders early on selected Dr. Tanzi as chairman. The trio of families knew that as a 22-year-old lab technician Dr. Tanzi had been a part of the team of James Gusella that discovered the gene implicated in Huntington’s disease. (Dr. Gusella himself was only 25.) Dr. Tanzi has been investigating human neurodegenerative diseases since 1980 and has cofounded two biotech companies currently developing new therapies for treating Alzheimer’s. He has co-authored over 285 research articles, as well as a book, “Decoding Darkness: The Search for the Genetic Causes of Alzheimer’s Disease.”

“We knew Dr. Tanzi was our man,” Mr. McCance was quoted in MassGeneral Magazine.

The CAF describes itself as “a venture capital approach to Alzheimer’s research.” One hundred percent of contributions go to research, because administrative expenses (including the gathering at Farm Neck) are paid for by the founders.

What can you do to decrease the risk?

Unless a cure for Alzheimer’s Disease is found, no one can reduce the risk of AD to zero. Half of all persons over 85 will have the disease. Many factors combine to create AD risk, including genetic mutation, traumatic brain injury, stroke, and stress. However, some lifestyle choices, according to Dr. Rudolph Tanzi, may increase the odds in your favor. Here is some of his advice:

° Physical exercise. Stay active, keep moving.

° Eat a healthy diet. Heart-healthy foods also may reduce the risk of AD.

° Reduce stress, which can stimulate the brain’s defenses and produce excess Abeta.

° Get enough sleep, at least 7 hours. Uninterrupted, deep sleep is best, as that is when short-term memories are consolidated into long-term memory and the production of amyloid proteins is shut off.

° Social engagement. Interact with others.

° Intellectual stimulation. Take a course, attend a seminar, play challenging games, solve puzzles.

° Expose yourself to new things. Make new synapses to back up your neural network.