At first one tree falls. No one notices it in the dense, majestic forest of memory. Then another tree falls, and another, and many trees collapse. Bald patches of memory appear, meanings that lived within them flee in alarm. The forest is erased. Here and there a dried-out stump remains. Who are you? My son? Nice to meet you. Who are you?
About 5.7 million Americans live with Alzheimer’s disease; 5.7 million people whose minds are becoming depleted, whose memories are crumbling into dust, their personalities falling apart. The number in Israel is 150,000. With increased lifespans, the number of the afflicted is anticipated to rise: By 2050 there are expected to be 13.8 million Americans who suffer from Alzheimer’s. The emotional burden is intolerable. The economic burden is immense. For decades, scientists around the world have been researching the disease, tens of billions of dollars have been invested in research – with nothing to show for it. No treatment, no medicine, no relief. The only medication that’s approved for use affects the symptoms of the disease for only a few months.
Occasionally, there is a media report about a seemingly promising breakthrough or about a success in an experiment using laboratory mice, but in the end the hopes are dashed. Now, after the failure of more than 400 experiments conducted around the world, some of them in the first stages, others at the stage of tests on humans, and as companies shut down the development centers that are working on Alzheimer’s – doubts are beginning to arise. Is it possible that the direction of the research was wrong from the start? Was it a mistake to focus on a single theory that was supposed to explain everything? Most scientists continue to espouse the conventional theory and explain every failure of experimentation individually; many, however, maintain that the field has reached a dead end and that a paradigm shift is essential.
Alzheimer’s is the most frequent cause of dementia, which refers to a significant decline in cognitive functioning. Other possible causes of dementia include vitamin deficiencies, depression and reaction to medication, among others. It’s a disease that develops gradually. Initially the short-term memory is affected, then the long-term memory and, with time, other cognitive functions are also impaired, such as orientation in time and space, the ability to make plans and others. In the stages that follow, motoric functions are also diminished. All these functional changes are manifestations of physical changes that occur in the brain, first in the hippocampus, which is responsible for creating new memories, afterward in additional regions. Slowly and gradually, nerve cells are damaged and degenerate, and the brain shrinks progressively.
Two types of Alzheimer’s are known. One is hereditary and rare (affecting a small fraction of those who are ill). It starts at an early age (30 to 40) and is caused by a few dozen genes, which have been identified. The causes of the second, which appears at an advanced age, are not so clear, so it’s termed “random.” Random Alzheimer’s also has a genetic component, but with this type of disease the critical importance lies in the individual’s way of life.
The dominant research hypothesis for almost 30 years points an accusing finger at a protein called amyloid beta, whose accumulation in the brain is considered the primary cause of the disease. It’s produced in the nerve cells and creates plaques between them, which then disrupts neuron communication and debilitates the nerve cells, leading to loss of the cognitive abilities. The existence of amyloid plaques in the brain is the characteristic sign of Alzheimer’s and distinguishes it from every other dementia condition. The “amyloid hypothesis” began to flourish after it emerged that it derives from a longer protein and when it was discovered that all the more than 150 mutations that appear in hereditary Alzheimer’s are involved in the derivative process.
This hypothesis encounters two principal difficulties. First, there is no full correlation between the existence of the plaques and cognitive abilities. Many people have amyloid plaques in their brain, yet they are cognitively sound. Second, none of the hundreds of treatments that succeeded in reducing or removing the plaques from the patients’ brain was able to restore, or at least to slow down the loss of, cognitive abilities. Still, the amyloid hypothesis remained the dominant one.
Over the course of time, researchers discovered the involvement of another protein, tau, which creates tangles in the nerve cell before its death. The hypothesis was accordingly updated: The amyloid plaques set the process in motion, the tau tangles conclude it. Not even the fact that patients were not cured even when the tau was damaged was able to dislodge the hypothesis from its premier status. Why is that so?
Despite a growing number of failures, only a minority of scientists are trying to think differently about the disease. Many of them admit that they find it difficult to get their studies published, and say they have been the brunt of criticism – and, worse, have been ignored. Two years ago, for example, 33 scientists and physicians published an article urging that notice be taken of the hundreds of findings that have been published over the years pointing to a connection between certain bacteria and viruses, and Alzheimer’s. These findings propose not only a circumstantial connection – for example, that people who suffer from herpes are at greater risk of falling ill with Alzheimer’s – but a genuine causal connection: that parasites are directly involved in the disease’s development.
When cells are infected with herpes, or when the brains of young mice are infected with salmonella, amyloid plaques form; in the brains of people who died from Alzheimer’s, herpes DNA is found exactly in the places where amyloid plaques exist; and so on. Discoveries like these led to a hypothesis that amyloid’s natural role is to protect the cells against parasites, and that the problem arises only when it fails in that task. The solution, according to this approach, is ridiculously simple: antibiotics or antiviral medication to eradicate the parasites. The fact is, proponents of the approach say, that people who are treated with antiviral medication are 10 times less at risk of contracting Alzheimer’s. Imagine that.
Even so, the picture is probably more complicated. Alzheimer’s – like cancer – is apparently not one disease. Its causes may be multi-diverse, so the medications and solutions also need to be diversified and coordinated, according to the causes and circumstances. It’s possible that for Alzheimer’s to develop, a combination of several factors is required. Accordingly, it’s important for more and more scientists to embark on new roads and to look at the subject from different angles.
Among those who are pressing for change, two Israeli researchers stand out: Inna Slutsky from Tel Aviv University, and Michal Schwartz from the Weizmann Institute of Science in Rehovot. Each of them begins from a different point of departure and proposes new insights that have the potential to free the field from its condition of stagnation.
Prof. Slutsky, from TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience, believes that conceptual ideas are difficult to uproot, particularly after substantial resources have been invested in them.
“The scientists who still cling to a hypothesis naturally have explanations for the difficulties,” she says with a smile. “Until recently, amyloid plaques in the brain could only be discovered in an autopsy. Because Alzheimer’s takes 15 and even 20 years to develop until the cognitive failures reveal themselves, the scientists argue that an autopsy also turns up plaques in the brain of people who haven’t yet developed the symptoms, but would certainly have developed them if they’d lived a few years longer.
“In contrast,” she continues, “people who manifest cognitive failures and are therefore diagnosed with Alzheimer’s, are already in the midst of the disease, about 15 years after the amyloid plaques were formed and set the disease in motion. The damage that was caused to the brain during those years is already too great, so removing the plaques doesn’t work.”
The door is shut after the horse has already bolted from the barn. Too late.
Slutsky: “Yes, that’s the argument. According to this explanation, amyloid is definitely the right goal, and the parasites that were developed against its plaques are worthy. But the diagnosis needs to be made far earlier, when the individual is 50, for example, long before the signs of Alzheimer’s dementia are manifested. The fact that today there are imaging technologies that can detect amyloids in the brain of a living person, creates the possibility that we can begin to treat people in which such plaques are discovered long before they show signs of dementia and before destruction begins in their nerve cells.”
But who’s going to agree to be treated with medications even before he’s been found to have Alzheimer’s?
“Other people claim that the failures arise because the model of the mice isn’t good enough. I think it’s easier to pin the blame on the mice than to ask where we went wrong. It’s not easy to admit that the approach was faulty. It’s not reasonable that this amyloid that everyone is talking about is the only cause of the disease. The fact is that hereditary Alzheimer’s, which entails a flaw in the genes that are involved in the production of amyloid, takes at least 30 to 40 years to develop. The accumulation of amyloid, then, is only a product of another disruption in the brain. Therefore, I have no doubt that the approach that focuses on the removal of amyloid plaques will not bring about the solution we seek.”
Slutsky began to do research on Alzheimer’s after years of studying how nerve cells transmit, encode and preserve information. “When I entered the field of Alzheimer’s,” she relates, “and I started to read articles, I was flabbergasted: For every article that presented a particular result, there was another that showed the exact opposite. Innocently, I thought that if we wanted to understand Alzheimer’s disease, we had to first understand the depth of memory mechanisms, and then examine how they were impaired in the disease. But I discovered that this was not the approach at all. At the time, the majority of researchers came from biochemistry, pathology and genetics, and they immediately focused on the disease’s well-known pathology. From the biochemical point of view, every possible aspect of amyloid beta was studied – its structure, the characteristics of the plaques it creates and how it produced itself. Generically, all the mutations related to the hereditary disease were discovered, and also the mutations that increase the risk of random Alzheimer’s.
“What amazed me is that the brain was studied as though it’s an organ like any other, as though it were the liver, for example: It’s made into a mash and the proteins in it are examined, as well as the genes responsible for them, in order to understand how it works. For years, no one considered the fact that the brain has a distinctive role involving the transmission of electrical signals. I was amazed to discover that electrophysiological methods were not used in the study of Alzheimer’s, as is done in the case of other neurological diseases. Can you imagine someone researching epilepsy or Parkinson’s without examining the electrical signals in the patients’ brains? Somehow, Alzheimer’s eluded the standard research approaches for neural networks.
“In the past 50 years, tremendous progress has been made in the study of memory. We discovered how short- and long-term memories are created, where they are stored and so on. Yet, with regard to a disease that involves such a difficult memory problem – all these insights were ignored. In my eyes, if the basic science shows us that memory depends on the electrical activity of the neural network, we should be capable of identifying the electrical signature that characterizes Alzheimer’s and of treating it.”
So now we need to go back to the drawing board, and begin at the beginning?
“No. But we need to open our minds and ask more basic questions. Because the research that concentrated on the biochemical field hasn’t worked, that approach has to be dropped and a new era launched. From my point of view, proteins exist in nerve cells in order to enable their electrical activity. So I thought that if we knew what the normal function of amyloid is in the brain, we might understand what the first stage is that causes memory problems.”
Previously, wasn’t the normal physiological function of amyloid beta known?
“Overall, it has a role in the regular transmission of electrical signals in the hippocampus, in preserving the plasticity of the nerve cells and in creating memory. For that, a certain level – balanced – of amyloid is needed in the cells. We discovered not only that at a high level, it’s problematic, as occurs in Alzheimer’s, but that an excessively low level also disrupts communication.”
Slutsky discovered, then, that amyloid affects the regular electrical activity in a healthy brain, and that, surprisingly, the opposite is also true: that normal activity in the brain affects the production of amyloid. Amyloid, it turns out, is produced in two forms, short and long. It’s the latter that’s problematic. The long amyloid is the “bad” type that accumulates and produces the plaque; the “short” type is “good” – and they are in a state of equilibrium. Most of the mutations that cause hereditary Alzheimer’s encourage the production of the long, “bad” amyloid.
“When we measured the activity in a healthy hippocampus,” Slutsky notes, “we saw that when the rate of electrical activity is high – a condition that characterizes learning and memory creation – a great deal of ‘good’ as compared with ‘bad’ amyloid is produced.”
Is this the reason for the recommendation that we learn new things – a language, a new sphere of knowledge, etc. – in order to prevent Alzheimer’s? Because, when we encourage the electrical activity that’s entailed in learning and memory, we encourage the production of “good” amyloid and inhibit the “bad”?
“I don’t have a simple answer to that question. I can only say that I hope that in the years ahead we will succeed in discovering certain patterns of ‘good’ brain activity and will be able to understand how to preserve them through learning, nutrition or physical activity. In recent years, articles have been published about people who suffer from ‘mild cognitive impairment’ [MCI], a condition that is usually seen as a pre-Alzheimer’s stage. When their electrical pathology was treated, their memories improved. Naturally, I found that very encouraging.”
For Slutsky, a key concept is “homeostasis,” which is disrupted in diseases such as Alzheimer’s. Homeostasis is a basic life principle, and refers to the maintenance of a stable internal environment, even in the presence of changes that are occurring in the external environment. Blood pressure, saline levels and body temperature are all maintained in the body at quite steady values, and any disruption or deviation from them activates mechanisms that restore the system to the stable condition. The classic example of this kind of mechanism in the human body is the secretion of insulin after a meal, thus preserving sugar levels within the normal range. An analogy from technology would be an air conditioner that is set to a goal value, such as 24 degrees C (75 degrees F). When the temperature in the room deviates from that value, the air conditioner receives an order to cool or to heat, and the temperature returns to the desired value.
A healthy brain works in the same way, Slutsky relates. In a series of well-known experiments that measured electrical activity in the brain of a rat, one of a rat’s eyes was caused to be closed, and, as expected, the electrical activity in the region of sight plummeted. Amazingly, though, two days later, electrical activity in the region returned to its original level, even though the eye was still closed. In other words, the system recovered even after the jolt it received.
“We, too, showed similar recovery in a network of nerve cells from the hippocampus,” Slutsky says. “That means that the neural network has mechanisms that are able to preserve its electrical stability, even when it undergoes dramatic changes. That stability is one of the basic characteristics of a healthy brain, and in effect it’s a condition for its health.”
You talk about stability, but the brain is an organ that is supposed to change in response to circumstances.
“That’s just the point. There’s a game here between two forces: change and stability. The possibility of adapting to the environment, and the ability to create and preserve memories, are dependent on the flexibility of the neural network. The danger in a flexible system is that it has an inherent tendency to instability, and therefore the brain developed mechanisms of homeostasis, which have a stabilizing role.
“Our hypothesis,” she continues, “is that in Alzheimer’s, a disruption occurs in the homeostatic control of the neural circuits connected to memory and learning. Our preliminary results suggest that the genes known to be involved in Alzheimer’s are connected to that control. We discovered, for example, a protein that’s involved in determining the goal value in the hippocampus – that is, the value according to which the system organizes itself for a particular rate of electrical activity. Any disruption of this value diverts the system to an abnormal state that harms plasticity and memory, and we are looking for a way to reset the value to its original state.”
The fact that the scientific world’s attention has been drawn to the pathological electrical occurrences in the brain of Alzheimer’s patients has recently yielded several interesting findings. For example, a study that traced electrical activity in the brains of dozens of random Alzheimer’s patients showed that 40 percent of them had epilepsy-like attacks during sleep. Moreover, the cognitive condition of those who suffered such attacks deteriorated far more rapidly than that of people who did not experience them. In other words, there’s a connection between the electrical pathology and the deterioration of memory.
It recently emerged that this irregular electrical activity appears even in the brain of people who are on the brink of the disease’s outbreak (those who have only just started to display signs of dementia that afterward turn out to be Alzheimer’s). If so, the possibility might exist for early identification of the disease, even before the appearance of the hard symptoms of memory loss and the creation of amyloid plaques.
Slutsky has similar thoughts. “On the basis of our approach, namely that the primary cause of Alzheimer’s – or at least one of the primary causes – is a failure of the brain’s homeostatic control, we want to develop a method for early diagnosis of the disease. The idea is to give the brain a serious jolt and then measure how quickly the system returns to its previous condition. The time it takes for a return to the point of equilibrium might be a good gauge for the health of the brain and thus serve as a tool for an early diagnosis of Alzheimer’s.”
Isn’t that a test that’s liable to be somewhat traumatic?
“Yes, but it would be meant to be brief. It’s like the principle of the test for diagnosing diabetes. The patient is given large amounts of sugar, which is especially unhealthy, in order to examine how he copes and how long it takes him to return to his normal equilibrium. The research direction in our case is still in preliminary stages, because we’re still concentrating mainly on understanding the basic mechanisms of memory and of homeostasis.
“When you use basic science, you can’t fail. Go right, you’ll find something interesting; go left, you’ll find something there, too. You’re not tied down to a situation in which you have set out to find a medication – that will always produce a bias. So from my point of view, it will be perfectly fine even if my theory about the disease’s development is proved wrong. Negative answers, if they’re grounded, also move us ahead toward the solution. The critical thing is not to be imprisoned by convention.”
‘Border control’ barrier
Another scientist who definitely refuses to be in the thrall of convention is Michal Schwartz, from the neurology department of the Weizmann Institute. Prof. Schwartz was one of four leading scientists whom the prestigious journal Nature Medicine recently asked to try to cut through the confused web of Alzheimer’s studies. She, too, believes that the problem with the research done to date is that it has focused wholly on treating the amyloid plaques and the tau tangles, which are considered causes of the disease. Schwartz turns the spotlight in a completely different direction: the immune system.
“This is a complete paradigm shift,” she says. “According to our approach, Alzheimer’s is a manifestation of a decline in the general functioning of the immune system. Throughout a person’s life, this system services the brain and maintains its equilibrium. When it’s weakened, which is what happens in old age, it allows Alzheimer’s to develop. It follows, according to our conception, that, irrespective of the disease’s preliminary causes, its cure must focus on the immune system.”
The immune system is commonly portrayed as an army that’s fighting intruders that have infiltrated the body. But the system has additional roles, Schwartz explains. “Immune cells circulate in the blood and monitor the body, and whenever a deviation from equilibrium is detected – the invasion of a foreign element, the appearance of a pre-cancerous cell, the accumulation of waste or damage to the tissue – they go into action. For years, it was thought that the brain isn’t subordinate to the supervision of the immune system, and that it constitutes territory separate from and independent of the body. It was known that in all the degenerative diseases of the brain – Parkinson’s, ALS [Lou Gehrig’s disease], Alzheimer’s – an inflammation of the brain appears, meaning a massive presence of the immune system there, and that phenomenon was interpreted to mean that when immune cells invade forbidden territory, pathology occurs.”
“Inflammation,” it bears noting, is a catchall name for a vigorous reaction by the immune system, not only in the wake of an invasion of bacteria but also in cases of tissue damage. For years, Alzheimer’s patients were given anti-inflammatory medications in order to eradicate the immune cells that penetrated the brain – but not only did that not help, in many cases it aggravated the situation.
“These findings,” Schwartz notes, “were consistent with our insight that immune cells in the brain are not necessarily a pathological condition, and that their presence in the brain of an Alzheimer’s patient is not the cause of the disease but rather a manifestation of the system’s normal attempt at healing.”
Why that attempt is unsuccessful with Alzheimer’s – that’s what Schwartz decided to find out.
The basic idea, then, is that far from there being a disconnect between the brain and the immune system, there is a continuing and necessary connection between them.
Schwartz: “Exactly. Although the brain has special cells – microglia – that are responsible for its ongoing maintenance, in a situation of distress these permanent workers are joined by ‘temps’ from outside: immune-system cells. They monitor the brain, and when something unusual happens – sabotage, accumulation of waste, etc. – they home in on the damage, recruit additional cells and take action to rehabilitate the damage.”
But how do the immune cells enter the brain? After all, the blood-brain barrier is supposed to prevent cells and large molecules from moving from the blood into the brain.
“That’s correct, and the existence of that barrier is what made the conventional approach – that immune cells can’t enter the brain – a carved-in-stone proposition. But we discovered a special interface that allows them to enter after all. It’s situated in the ceiling of the brain’s chambers, on the border between the brain fluid and the blood vessels, and it functions as a barrier that has ‘border control.’ Gatekeepers there allow or prevent the passage of immune cells into the brain, as needed.”
So now we come to Alzheimer’s. What is it that goes wrong?
“According to our approach, Alzheimer’s develops precisely when the immune cells don’t enter the brain as they should and don’t fulfill their role. Normally, they should remove waste – including the amyloid – and dead brain cells. When they don’t do that, amyloid accumulates, and a chain of events begins that causes several kinds of damage. So that, actually, not only is it not right to get rid of the immune cells in the brain – but the very opposite is true: More cells need to be mobilized and allowed to enter in a controlled way so that they will at long last remove the wastes.”
What prevents immune cells from entering a brain ridden with Alzheimer’s?
“The border crossing is blocked. One of the reasons for this is that the gatekeepers – the cells that are supposed to excrete materials that open the crossing – are inhibited. As though they’d been handcuffed. That inhibition occurs in old age and even more in Alzheimer’s. We’ve been able to discover one of the proteins that’s responsible for the inhibition, and when we neutralized it we released the cells and we succeeded in doing a reverse of Alzheimer’s.”
What do you mean by “a reverse of Alzheimer’s”?
“When we released the gatekeepers, we allowed immune cells to enter the brain of mice with Alzheimer’s, and the mice’s cognitive abilities were rehabilitated.”
And that’s in the wake of intervention in the immune system, not in the brain.
“Exactly. That means that the immune system is the key to curing Alzheimer’s, and that’s the direction we’re following. In a certain sense, it’s as though we’re ‘rejuvenating’ the brain.”
It sounds something like the promise of anti-aging – smoothing wrinkles, stretching the neck, rejuvenating the brain.
“Of course, we’re not talking about an anti-aging product. Our research, which has been ongoing for 20 years, started as totally basic science that set out to challenge the existing paradigm. That ambition generated tremendous opposition to us, but also led us to develop an approach that differs in principle from everything that’s been done until now in the field. The laboratory results offer good reasons for optimism. We could hardly believe the preliminary results. And therefore we truly believe that it will be possible to ‘rejuvenate’ the brain, in the sense of treating the diseases of dementia or at least slowing the deterioration.”
Another reason for optimism is that Schwartz’s treatment is very similar to the anti-cancer medication that earned its developers (James P. Allison and Tasuko Honjo) the Nobel Prize this year. Both treatments are based on the understanding that the problem, at least in part, and the solution as well, lie in the functioning of the immune system. “Because of the similarity between the approaches,” says Schwartz, “we expect it will be possible to arrive at clinical application of our treatment relatively easily.”
You talk about a paradigm shift, but your treatment, too, which arose from the new paradigm, ultimately removes the amyloid plaques, and if so, it’s no different from everything that’s been tried to date.
“It’s indeed important to clarify this point. Our treatment mobilizes the immune system, which not only removes the amyloid plaques. It’s also responsible for removing dead cells, healing damage and for additional maintenance matters of the brain. We’re talking about a range of cells, and a range of materials excreted by them, and it’s not even certain that we know them all. That’s what’s so fine about our approach: that even without understanding fully what the first reason for Alzheimer’s is, or the second or the third, it’s sufficient if we strengthen the immune system in order to succeed, because we are using the brain’s natural healing system. It’s not geared to treat a particular element of Alzheimer’s, necessarily; it knows how to execute the totality of the processes.”
It’s actually a “rehabilitation package.”
“Exactly. The moment the immune system is released from the inhibition, we simply allow it to do its work, and it restores the brain to its equilibrium. Therefore, I think that a medicine for Alzheimer’s is a matter of the coming decade.”
Less sugar, more sleep
The answer to the question of whether Alzheimer’s is a genetic disease is that it is. The earlier the disease appears, the stronger the genetic component, and the later it appears, the more decisive the role of one’s lifestyle. Because the disease is presently incurable, it’s useful to take note of possible ways to prevent it. Studies have found a number of elements that influence the disease’s development, from which recommendations for behavior are derived. Generally speaking, the recommendations are for the same way of life that’s appropriate for preventing cancer and heart disease, though mechanisms have been found that link some of the elements directly to Alzheimer’s.
The two principal recommendations that have proved effective in preventing the disease or in inhibiting deterioration in its initial stages, are aerobic physical activity (at least 30 minutes a day, three to four days a week) and nutrition based on a Mediterranean diet (fresh fruits and vegetables, nuts and grains, olive oil, fish and dairy products, moderate amounts of poultry and of red wine, and a little red meat).
In recent years, sugar has been considered a primary risk factor, so much so that some call Alzheimer’s “Type III diabetes.” Recently, the results were published of a study that monitored 5,189 people over a decade. It found that the higher their blood sugar levels, the more rapid was their cognitive deterioration. This correlation also applies to people who are not diabetics or prediabetes, but are in what’s considered a normal range. On top of this, studies suggest that the most common medication for Type II diabetes – metformin (also known as Glucomin or Glucophage) – protects the brain from Alzheimer’s, Parkinson’s and other neurodegenerative diseases. Evidence exists that even nondiabetics can benefit from taking the medication. However, because it’s a generic medication and therefore astonishingly inexpensive, pharmaceutical companies have no interest in investing in this research direction. Prof. Slutsky showed that a substance that’s very similar to metformin is involved in the homeostatic control in the hippocampus.
Other recommendations – whose effectiveness hasn’t yet been proven definitively but for which evidence has been found – include learning new things (auditing lectures, learning a new language and the like) and forging social ties. Their underlying rationale is the creation of “cognitive reservoirs”: The cognitive activities influence the memory by developing ramified neural networks that represent reality, so that even if damage is caused at one place because of amyloid plaques, the extensive network can propose “alternative routes.”
Finally, it’s never an exaggeration to emphasize the importance of sufficient sleep. Studies have found a connection between sleep and wakefulness cycles and the accumulation of amyloid beta plaques in the brain. Brain scans have discovered an accumulation of the plaques in the hippocampus even after one night without sleep. In parallel, it emerged that amyloid proteins are ejected effectively during sleep and not during wakefulness. It follows that lack of sleep can cause or spur the development of Alzheimer’s – a conclusion that is consistent with Prof. Schwartz’s hypothesis regarding the involvement of the immune system, which is active mainly at night, in curtailing the disease’s development.