New Israeli study links brain hyperactivity to Alzheimer’s

An Israeli research team has announced new findings that link Alzheimer’s disease to brain hyperactivity and says its research helps explain why so many patients who have this debilitating disease run a high risk of seizures.

While the amyloid-beta protein involved in the development and progression of Alzheimer’s seems the most likely cause for this neuronal hyperactivity, how and why the elevated activity takes place hasn’t been explained until now.

“These are truly exciting results,” said Inna Slutsky, who led the Tel Aviv University (TAU) research team.

The study, recently published in Cell Reports, shows that the guilty party in enhancing neuronal activity in Alzheimer’s patients is a molecular mechanism involving the amyloid precursor protein (APP). APP is well-known for its role in producing amyloid-beta, but it also acts as a receptor for amyloid-beta.

Elevated activity in the hippocampus — the area of the brain that controls learning and memory — has been observed in patients with mild cognitive impairment and early stages of Alzheimer’s disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early-onset Alzheimer’s disease.

Now, the Israeli researchers found that the binding of amyloid-beta to pairs of APP molecules triggers a change and causes elevated brain hyperactivity.

“Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons,” said neuroscientist Slutsky, who last year reported that bursts of gentle electricity can slow the progression of Alzheimer’s.

With this added piece of the puzzle, the potential for restoring memory and protecting the brain is greatly increased.

Building on earlier research

The Israeli researchers’ groundbreaking discovery was not made overnight. The study was actually launched five years ago, following the researchers’ discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve-cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected “normal” neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta.

“This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity,” Slutsky said.

The researchers — whose study was supported by European Research Council, Israel Science Foundation and Alzheimer’s Association grants — collaborated with Joel Hirsch of TAU’s faculty of life sciences, Dominic Walsh of Harvard University and Ehud Isacoff of UC Berkeley to harness a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signaling in neural cultures, brain slices and mouse models.

They used highly sensitive biophysical techniques based on fluorescence resonance energy transfer between fluorescent proteins in close proximity. This allowed them to see that the binding of amyloid-beta triggers a change in APP to APP interactions, leading to an increase in calcium flux and higher glutamate release — in other words, brain hyperactivity.

Protecting the brain

The mystery of Alzheimer’s is far from being figured out. And the Israeli researchers are not resting on their laurels.

“We have now identified the molecular players in hyperactivity,” said Slutsky.

“TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain.”

Previous studies by Lennart Mucke’s laboratory in California strongly suggest that a reduction in the expression level of “tau” (microtubule-associated protein), another key player in Alzheimer’s pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models.

“It will be crucial to understand the missing link between APP and ‘tau’-mediated signaling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signaling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer’s disease,” Slutsky said. 

For the millions of people living with the disease and the millions more caring for the victims, any further understanding of why Alzheimer’s happens is a silver lining in a black cloud. 

The powers and pitfalls of the boomer brain

“I’m reading a great book about the middle-aged brain,” I recently told a friend, “but I can’t remember the title.”

Welcome to the boomer brain. Grasping for names. Walking into a room only to wonder what you went there for. Getting halfway through a book before realizing you’ve read it before.

It’s not all bad news, however. According to the book whose name I couldn’t remember — “The Secret Life of the Grown-up Brain” (Penguin, 2010) — not only does the boomer mind have advantages that can’t be found in a younger brain, but it is also possible to strengthen the brain in our middle years and beyond. This hopeful message comes from author Barbara Strauch, a science and health editor at The New York Times who interviewed dozens of scientists to research her book.

First, the bad news: Middle-aged brains (roughly between the ages of 40 and 68) have slower processing speeds than younger brains. That’s why it takes us longer to learn a new language or adapt to a new technology. We also get distracted more easily and have poorer episodic memory — the ability to recall recent events. 

And, of course, we often find ourselves mired in what Strauch calls “The Swamp of Lost Names.” We’ve all had the experience of stumbling when it’s time to make an introduction or greet an old acquaintance, even with people — and names — we know well. According to Strauch, this stems from a problem with retrieval, not storage. 

“It’s like trying to find the right book in a well-stocked library,” she writes. “Forgetting names is part of normal aging.”

It’s hard not to jump to worrisome conclusions when we have these brain blips, but Moshe Bar, director of the Leslie and Susan Gonda Multidisciplinary Brain Research Center at Israel’s Bar-Ilan University, assured me that they are normal. 

“Forgetting is perfectly natural and generally in itself not an alarming sign,” he told me via e-mail. “Do not forget (no pun intended) that as we grow older, we also tend to be busier (up to a certain age, of course) and have more on our mind. Stress and sleep deprivation, for example, can also add to forgetting. …Clinical dementia requires much more than occasional forgetting of names, and generally includes significant impairment not only in memory but also in language, attentional allocation, decision making and more.”

OK. We get more forgetful, and it’s not a sign of dementia. And here’s the good news, according to Strauch: “Our middle-aged brains are surprisingly competent and surprisingly talented.” 

Boomers, she discovered, are best able to appreciate complexity, detect patterns and exercise good judgment. 

“Faced with information that in some way — even a very small way — relates to what’s already known, the middle-aged brain works quicker and smarter, discerning patterns and jumping to the logical endpoint,” she writes.

Drorit “Dee” Gaines, a post-doctoral trainee in the field of neuropsychology at the UCLA Longevity Center, notes that executive functioning excels in middle age. 

“We are better at understanding the full meaning of a complex situation, better at grasping all the details, and getting the ‘main picture,’ ” she explained. “We are also more contemplative, careful in our weighing and processing a situation, a scenario. … We have more stored knowledge we can utilize to our advantage when we approach a cognitive task and often incorporate this pre-existing knowledge in our ‘executive’ processing.” 

Strauch also reports that we can build up our cognitive reserve — a protective “reservoir of strength” that makes the brain more resilient and better able to tolerate damage. And we can do so at any time in our lives — including middle age and beyond. 

It was once thought that the adult brain cannot change, but scientists now know that our actions can literally change the arrangements of our brains. As Strauch explains, “If two brain cells are activated at the same time, they will actually change their structure, form stronger connections, letting us form memories and learn.”

Scientists are still trying to determine exactly how to boost cognitive reserve, but Strauch reports that some consensus has emerged. Education is one factor. A study done at Columbia University found that those with higher levels of education or more complex occupations were less likely to show signs of dementia.

Cognitive activity is another factor. While the effectiveness of “brain building” programs has not yet been established, it seems engaging in mental activity that becomes progressively more difficult can help boost cognitive reserve. 

Perhaps the most established method of building cognitive reserve is physical activity. Aerobic activity appears to stimulate the growth of new brain cells — at least in mice. And it definitely increases blood flow in the dentate gyrus, an area in the brain that is crucial to memory. Strauch cites a study showing that participants over age 60 who did regular stints of aerobic exercise for six months showed increased brain volume.  

Gaines said that physical activity engages “multiple brain systems, such as sensory, motor, balance and coordination, breathing and movement regulation. And for more complicated, pattern-based exercises [such as tai chi and yoga], memory and executive functions [are also engaged].”

Social activity is beneficial, too, although we don’t know exactly why, according to Bar. 

“Perhaps the constant cognitive demands involved in such interactions, perhaps the good feeling associated with being with friends,” he speculated. “But the bottom line is that they help maintain the cortical volume of the very regions that lose volume with aging.”

So what are we to conclude about the boomer brain? It’s a trade-off. But in some areas at least, according to Bar, “[T]he increased experience that comes with aging more than compensates for the loss of neurons.” 

An Israeli Workout for the Brain

What do limousine drivers, breast cancer patients and retirees have in common? They’re all the beneficiaries of the applications developed by CogniFit, an Israeli company.

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“Our products essentially complement what we do at the gym,” said professor Shlomo Breznitz, CogniFit founder and president. “We want to convince people — particularly older people — that their minds need to be maintained just like their bodies.”

A renowned psychology professor and past president of the University of Haifa, Breznitz was recently elected to the Knesset as a member of the Kadima Party.
The company, which began with a handful of employees in a tiny office in the Tzipori industrial area in the Galilee near Nazareth, now employs 35 workers.
The first application Breznitz focused CogniFit on was driving. According to Mazal, driving is one of the most difficult tasks, because of both the speed at which drivers are traveling and the amount of information that needs to be processed quickly.

“If a driver is slow to process information, it exposes him to greater risks because he’ll be slower to understand road situations,” he said.

CogniFit’s product, FleetFit, assesses drivers’ information-processing capabilities, an assessment which is particularly useful in the insurance industry or with companies that possess large fleets of vehicles and drivers.

“We have a new agreement with risk and safety management company CEI in Philadelphia,” Mazal said. “They’re used by many of the major pharmaceutical companies who employ great numbers of drivers.

“Now they’re offering FleetFit to their clients — with the purpose being to identify which drivers of a specific fleet are at high risk, or to put it more bluntly: Which drivers are accidents waiting to happen?

“Based on the results, the company can then decide what to do with the driver — whether it be deciding to send him to a specific training course or replacing him,” Mazal said.

As effective as Flee
tFit and MindFit have reportedly proven to be, the application believed to have the greatest potential is Cognifit’s newest program, Back On Track. The application has been designed specifically for women who have undergone chemotherapy treatments for breast cancer and are experiencing the so-called “chemo fog” associated with cancer treatments.

One recognized possible side effect of chemotherapy is long-term cognitive impairment. Symptoms, in particular memory and concentration problems, are frequently reported by cancer patients treated with chemotherapy, even years after completion of treatment.

Back On Track was developed using patented scientifically based technology that has proven that active training improves the cognitive skills necessary for everyday activities. It includes a variety of tasks that were designed specifically to exercise the basic cognitive skills that are needed for daily functioning.

People experiencing the cogniti
ve effects of chemotherapy generally respond very well to focused rehabilitation efforts. Just as a person goes to the gym to keep their body in top shape, the brain needs to be exercised as well. Cognifit said Back On Track will engage the mind by exercising all the major cognitive skills and help to find ways to cope with cognitive deficits.

“While potentially, the treatment is good for people who have undergone chemo for any type of cancer, we’re targeting this specific group because of the high awareness of chemo fog among breast cancer patients,” said Mazal, adding that the treatment is currently undergoing clinical trials at an Israeli hospital.

Total Recall

Twice in the past couple of days, I’ve been in conversation and found myself grasping for a word. On both occasions, my 4-year-old supplied the word before I could come up with it. And, of course, there are the times that I walk into a room only to realize that I have no idea what I wanted to do once I got there. Are these natural lapses or early signs of something more sinister?

"We are all one day closer to Alzheimer’s disease," Dr. Gary Small says forebodingly in his book "The Memory Bible: An Innovative Strategy for Keeping Your Brain Young" (Hyperion, 2003). "Alzheimer’s and dementia begin forming in our brains much earlier than anyone previously imagined, even in our 20s."

Fortunately, we can thwart — or at least postpone — this progression.

"It is never too late or too early to protect our brain cells and delay memory decline," writes Small, who is the director of the UCLA Center on Aging. "By using games, puzzles and some new approaches to daily activities, we can improve our short- and long-term memory abilities and possibly prevent future memory loss and Alzheimer’s disease."

The good news about Small’s "anti-brain aging" program is that all of the recommendations are pretty basic. They do not require exotic terminology or elaborate equipment. The bad news is that change isn’t instantaneous. Beyond the memory tricks and techniques, the plan calls for making fundamental changes to diet, amount of physical activity and stress levels — easier said than done.

Launching into the book, I started with the memory self-assessment, which identified my degree of "memory challenge" as "moderate." (It took me four tries to correctly tally my score, so I guess my mathematical abilities would rate as "pathetic.") In another test, I was able to recall six out of 10 unrelated words 20 minutes after reviewing the list.

Small’s principal memory technique is called Look-Snap-Connect. "Look" means to truly pay attention. For example, most of us are so busy thinking of other things when we’re introduced to a new person, that we understandably can’t recall their name just minutes later. This step involves actively focusing on what you want to remember, taking time to absorb details and meaning. "Snap" refers to creating a mental picture of the information, such as visualizing a frankfurter to remember the name Frank. "Connect" involves combining mental pictures in a meaningful way, creating a story of sorts that will help you retain and access what you want to remember.

Another strategy is called chunking — dividing a large group of items into smaller groups or groupings with common characteristics. The "Roman Room" technique involves visualizing a familiar room and mentally placing items to be remembered — for example items on a grocery list or the topics of a lecture — in specific locations within the room. Small also presents the Peg Method as a way of "forever removing uncertainty about remembering numbers." I thought I’d try it to learn my husband’s Social Security number, but the method requires creating and memorizing visual images for each of the 10 digits, then linking the images in a story. That seemed like much more effort than simply memorizing the number the old-fashioned way.

When it comes to brain power, Small believes in the "use it or lose it" philosophy. He recommends "a daily regimen of mental aerobics," which can involve such activities as crossword puzzles, brain teasers and other endeavors that keep us mentally stimulated. He cites research that found that the risk of developing Alzheimer’s disease was three times lower in people who had been intellectually active during their 40s and 50s compared to those who hadn’t.

Beyond the techniques and the brain teasers, Small’s recommendations are the same ones we’ve all heard repeatedly for maintaining wellness and staving off disease: following a low-fat diet, reducing stress, staying physically active, getting sufficient sleep, balancing work and leisure, avoiding tobacco and other drugs, and engaging in meaningful activities and relationships. He does offer some specific dietary recommendations, including taking 400-800 units of vitamin E and 500-1,000 milligrams of vitamin C daily, as well as eating foods — such as avocado, salmon and walnuts — that are rich in omega-3 essential fatty acids.

Will it make a difference? I tried to memorize another list of 10 words — and, this time, I could remember nine of them. But having just finished the book, it’s too early for me to tell how much of a change it will make in the long run. And much of that depends on how thoroughly I follow through on the book’s recommendations. So I made a list of the steps I plan to take as part of my new memory regimen. But just in case the list gets lost, I’m also telling my 4-year-old.

The UCLA Center on Aging holds classes in improving memory. For more information, call 310 794-0676.