Alzheimer’s: Dashed hopes, new directions


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Alzheimer’s disease is part of your future — if it’s not already part of your present.

Either you or someone in your family will contract it, or you’ll know someone who will. And even if you don’t, the disease will cost you financially as it ravages our health care and social support systems.

Alzheimer’s is, at least so far, an irreversible condition: The brain clogs with twisted protein molecules that inflame its cells and muddle thoughts. First your memories disappear, then your personality disappears. Then, it’s too late. Alzheimer’s kills you.

The disease’s signs are well-known. Beta-amyloids, which are fragments of protein molecules, build up in spaces between brain cells and disrupt communication among them. Normally, the body washes away these fragments through normal housecleaning. But in Alzheimer’s, beta-amyloids stick together and make pebbles in the brain. The pebbles cause inflammation, which eventually kills brain cells.

Another signature is a tangle of protein fibers inside brain cells themselves. These tangles are made up of a protein called tau, which composes the microchannels that carry nutrients and neurochemicals around the brain. In Alzheimer’s, the tubes disintegrate and the debris accumulates inside the brain cells.

Some researchers conjecture that Alzheimer’s makes its first assault on a small part of the brain stem called the locus coeruleus. This area releases norepinephrine, the brain chemical that governs memory, attention and cognition. The locus also sends its tendril throughout large areas of the brain to regulate the brain’s blood vessels. Because it’s so connected to so much of the brain, the locus may be more susceptible to disruptions in various parts of the organ.

What is clear is that Alzheimer’s attacks the hippocampus early on, where the brain keeps short-term memories and routine processes. (“I can’t remember where I parked the car” or “I forgot how to operate the washing machine.”) Next, the disease moves to the cerebral cortex, the outer layers of the brain, and destroys the ability to speak, make judgments and regulate emotions. Finally, the illness eradicates the ability to perform routine physical tasks and control body functions.

CASELOAD ON RAPID INCLINE

In the United States, four new people every five minutes develop the disease. This year, 500,000 new cases will be diagnosed in the US alone. At current rates, the 5 million Americans now suffering from the brain disease could become more than 15 million by 2050.

Worldwide, almost 50 million people have Alzheimer’s. In Japan, with one of the world’s oldest populations, the rate of Alzheimer’s in people 65 and older rose from 1 percent in 1985 to 7 percent in 2008. According to the nonprofit Alzheimer’s Disease International, the number of cases globally will double every 20 years. Most of those will be in developing countries such as India and southeast Asia, where populations are expanding and people are living longer.

And there are other big numbers in play. Of the more than 400 Alzheimer’s drugs that have been tried, most have failed. A handful have been able to slow the disease’s progress, but none can cure it. The clinical trials required to test a drug’s effectiveness can cost $100 million or more. But drug companies, from start-ups to Big Pharma, stay on the hunt for the key to what could be an annual global market reaching into the tens of billions of dollars.

Besides, Alzheimer’s doesn’t just afflict those whose brains stop working. An estimated 15 million Americans care for family members with the illness. More than a third of those caregivers report adverse effects on their own health, not to mention their incomes. If the 18 billion hours of care that these folks gave in 2016 were assigned an economic value, some estimates calculate it to be $230 billion — more than nine times McDonald’s total 2016 sales.

And then there’s the cost of paid care, estimated to be $259 billion in 2017 in the US alone. In 2015, the cost of care worldwide passed $800 billion, making the “Alzheimer’s economy” the 18th largest economy in the world, falling in just ahead of the Netherlands’.

US deaths from heart disease have fallen 14 percent since 2000; why have deaths from Alzheimer’s soared 89 percent over the same time?

WHAT CAUSES ALZHEIMER’S?

Part of the reason is that no one is exactly sure what causes Alzheimer’s.

The disease’s broken proteins are telltale. But why do proteins break down and stick together in the first place? And why have some people been found, on autopsy, to have lived with a brain full of amyloid plaques but showed no sign of mental abnormalities?

Researchers still aren’t sure. The best guess is that the interplay of several factors over many years culminates in the disease.

The one sliver of good news: 40 years ago, aluminum — an ingredient in everything from deodorants to cookware — was named as a culprit. Since then, the metal has been exonerated as the, or even a, cause of Alzheimer’s. The answer is far more complex.

Age is the greatest single risk factor. The older you are, the more time the mechanisms of the brain have to wear out or break down. It’s estimated that one in nine people in the US over 65 have Alzheimer’s; for people 85 or older, it’s one in three.

Diet is also a concern. The typical American diet of processed foods and “bad” fats gives the body less nutrition and more junk to process. After decades of dealing with foreign substances, a person’s ability to clear out the waste can begin to wane.

Two diets in particular have raised hopes. The Canadian Brain Health Food Guide and the MIND Diet both suggest eating mostly plant-based foods, fish, seeds, nuts and whole grains, with some variations between the two. Research linked the Canadian version with a 36 percent reduction in the risk of getting Alzheimer’s, the MIND Diet with a 53 percent drop.

Some researchers particularly cite vitamin D. Deficiencies of that vitamin are linked to poor mental performance and to greater risk and faster onset of Alzheimer’s. An international research team has linked six specific unsaturated fatty acids in key portions of the brain to Alzheimer’s.

The couch-potato lifestyle also may contribute. Physical activity helps flush wastes from the body. In fact, heart disease and Alzheimer’s often are found together. Stress also has been noted as a possible spark; head injuries may contribute.

The risk is even higher for dark-skinned people. Hispanics are 1.5 times more likely to contract Alzheimer’s; persons of African descent face double the risk of whites. The reasons aren’t known. One theory is that dark skin has a harder time absorbing vitamin D; other researchers point to the higher rate of vascular disease among these groups living the American lifestyle of inactivity and eating processed foods. However, a 2013 study found two genes in African-Americans that increase the risk.

Even common heartburn medications have been implicated. These so-called “proton-pump inhibitors” or PPIs are among the world’s best-selling drugs and their use is on the rise among elders. These concoctions have ingredients that cross the blood-brain barrier ­— the body’s filter that keeps dangerous compounds away from the brain — and may have impacts there that aren’t yet defined.

Two recent studies from Germany found that older adults who took the medicines steadily over 18 months or longer had between a 38 and 44 percent greater chance of coming down with Alzheimer’s than those who use PPIs rarely or not at all. Still, that doesn’t mean the drugs cause the illness; heartburn or acid reflux may just be another symptom of a different Alzheimer’s cause.

YOUR DNA PLAYS A ROLE

And, for some, there’s the genetic factor.

Risk genes, particularly a gene called APOE-e4, raise your risk of getting Alzheimer’s but don’t guarantee it. Inheriting APOE-e4 from one parent creates a risk; inheriting it from both parents heightens it by up to 20 times. This gene also might mean an earlier onset.

Deterministic genes more or less guarantee the disease and raise the probability that symptoms will show up before a person is 60 years old. Fortunately, this gene has been found in only a few hundred families worldwide and accounts for only about 1 percent of Alzheimer’s cases.

There’s another biological oddity that’s suspect. As men age, almost 20 percent of them begin to lose some Y chromosomes from their blood, especially if they smoke. The loss of Y chromosomes has been linked to some cancers. A 2016 study from Sweden’s Uppsala University has correlated the loss of Y to a greater likelihood of getting Alzheimer’s — as much as if a man is born with a genetic predisposition to the illness.

But perhaps the greatest controversy in the search for Alzheimer’s cause is the question of infection. Maybe the disease is caused by invaders.

This challenge to the dominant “amyloid hypothesis” was championed by 31 Alzheimer’s researchers around the world who wrote an open letter to their colleagues in March 2016. They argued that more than 400 clinical trials of drugs designed to break up amyloid plaques in the brain had failed to reverse attendant mental decline; maybe, they said, that it was time to look in a different direction.

The only reason that’s been found for the strain of amyloid implicated in Alzheimer’s is to clear infection. Therefore, perhaps the plaques are a symptom — an over-reaction to an infection — and not a cause. The 31 scientists argued that the herpes virus and chlamydia bacterium have been found in unusual concentrations in many Alzheimer’s patients and that the possibility of a link should be investigated. There also have been hints that, in a very few cases, the disease has been spread through surgery and blood transfusions. If that’s happened, that also suggests that a traveling infectious agent is to blame.

The “infection hypothesis” is getting traction, in part, because the search for an Alzheimer’s cure has been frustrating. To date, treating the disease has been limited to administering drugs that slow its inevitable progression.

Making matters worse, some drugs intended to ease symptoms actually seem to promote them. One called tramiposate was seen to “promote an abnormal aggregation of tau” proteins. Another, called donepezil, seems to accelerate mental decline in patients with a particular genetic variation.

With so many different factors seeming to collude in the cause, it’s not surprising that a cure has been elusive. But new research is bringing new hope.

Ironically, that hope springs, in part, from a recent series of well-publicized failures of new drug trials.

The drugs were designed to break up amyloid plaques, based on the assumption that getting rid of them would get rid of the attendant mental dysfunction. But last November, Eli Lilly reported that its drug had succeeded in breaking down plaques, but that the trial participants’ mental abnormalities continued unabated.

In February this year, Merck shut down the trial of its newest anti-amyloid compound, saying that the drug had “virtually no chance” of success.

This string of failures, and a spate of new research results into the disease’s progression, have led researchers to rethink their approach. They’re not abandoning the theory that protein breakdowns cause the disease. Instead, the new tack is to diagnose the illness and start treatment before symptoms even show up.

That’s become possible only lately. In the past, the only way to confirm the presence of protein clumps in someone’s brain was to autopsy the brain after the person died. But two advances indicate that early diagnosis — and, therefore, aggressive early treatment — could soon become the norm.

The first advance is the use of X-rays and positron emission tomography — PET scans — to find protein clumps in their early stages. Although the use of brain imaging to spot protein pellets dates back more than a dozen years, equipment and techniques have become refined enough to be reliable. (In March 2017, researchers used a special X-ray machine called a synchrotron accelerator to pinpoint changes in the brains of mice developing Alzheimer’s before protein plaques showed up. They found that the proteins causing plaques had a different structure than previously thought. The structure they discovered mirrors that of proteins that cause a condition called transthyretin amyloidosis, for which a drug has already been proven to slow the disease’s advance.)

But imaging is expensive, as much as $4,000 per patient, and insurance often doesn’t cover the cost.

The second gain was announced last June. Researchers at Rowan University, partnered with start-up Durin Technologies, claim to have developed a blood test that’s “100 percent accurate” in detecting the biochemical signatures of Alzheimer’s. The test boasts the added benefit of being able to distinguish without fail between Alzheimer’s and other causes of dementia, such as vascular disease or severe depression.

Now that the disease can be detected at earlier stages, drug makers are preparing to take their potential cures back into clinical trials — but now with volunteers who aren’t yet showing symptoms. Some analysts have compared the recent failed trials to testing a cancer drug on a terminal patient; even if the drug is effective, irreversible damage already has been done. Earlier treatment may prove the drugs’ effectiveness in stopping, or perhaps even reversing, the condition’s progress.

Accera, a Boulder, Colo.-based development-stage company, isn’t waiting to find out. It’s pursuing “the sugar hypothesis.” That idea states that Alzheimer’s is caused by brain cells’ failing ability to use glucose, the simple sugar that fuels the body’s processes. Accera entered a trial of its AC-1204 drug that’s designed to spark up the brain’s ability to metabolize sugar.
Now, though, the company has announced that the trial was a bust; the drug isn’t being well-absorbed by the body and Accera is back at the drawing board.

But the sugar hypothesis may gain strength from the surprising discovery that drugs that control diabetes show some power against Alzheimer’s.

BIG PHARMA TO THE RESCUE?

A 2014 study by Lancaster University tried the diabetes drugs lixisenatide and liraglutide on mice genetically engineered for the disease. It found that mice treated with the drugs improved their cognition. A follow-up test of liraglutide at Denmark’s Aarhus University found that people responded in the same way as Lancaster’s mice.

Even more promising, the drug metformin had the same results. Metformin is perhaps the most common drug, other than insulin, taken by persons with diabetes. Metformin is known to play a part in memory formation and also has been found to clear protein debris from brain cells.

Tulane University tracked 6,000 diabetic military veterans and found that long-term metformin users had 75 percent less incidence of Alzheimer’s than those who didn’t take it. Tests at Toronto’s Hospital for Sick Children showed that metformin improved memory in mice that don’t have diabetes.

But metformin is dirt-cheap — a month’s supply costs a few dollars — and clinical trials cost millions. So, drug companies have little incentive to test metformin as part of the process of asking the US Food and Drug Administration to approve it for use by Alzheimer’s sufferers.

Now, while scientists ponder the merits of amyloid, infection and sugar hypotheses, a better-known drug is also piquing interest: marijuana. A small, pre-clinical trial by the University of South Florida indicated that THC — the main active substance in marijuana — reduced amyloid plaques and eased mental muddle.

Research at the Salk Institute came to a similar finding. Scientists there saw evidence that THC and its companion chemicals in pot not only beat back protein deposits, but also quieted brain cells’ inflammation response to the amyloid stones.

It turns out that brain cells make chemicals very much like THC that are thought to help the cells communicate. To do that, the cells have receptors for THC-like chemicals.

The THC from marijuana can bind to those receptor sites and may prevent or reduce the inflammation of cells that may cause and sustain amyloid plaques.

However, a research project at Radboud University in the Netherlands found that marijuana had no effect on the behavioral symptoms of Alzheimer’s.

More research likely will clarify questions about which Alzheimer’s patients can benefit from marijuana and in what doses.

Another bit of hope from an unexpected source: A 2016 trial by scientists at the University of Manchester discovered that mefenamic acid, a common non-steroidal anti-inflammatory pain reliever, “completely reversed” memory loss and brain inflammation in mice genetically engineered to contract Alzheimer’s. Because this class of drugs is among the most prescribed in the world, the side effects are well-known. That could speed the drugs’ repurposing for Alzheimer’s treatment. Human trials are being planned.

But now drugs aren’t the only recourse in treatment.

Nature Cell, a Korean biotech company, is recruiting patients in the US for a clinical trial of its “Astro-Stem” process to culture stem cells that are injected into the body and develop into new brain cells. The goal is to slow the progress of the disease, especially if the technique is used with drugs that break up plaques and slow cell degeneration.

At the University of Queensland in Australia, scientists working with mice have shown that simple ultrasound technology may work better and faster than drugs. The researchers sent ultra-fast sound waves through the brains of mice with Alzheimer’s and found two results.

First, the sound waves shattered amyloid plaques into smaller bits. Second, the waves also weakened the blood-brain barrier for a few hours, allowing the protein debris to be flushed out of the brain and into the body’s general circulatory system to be disposed of in the usual way.

In 75 percent of the mice that were treated, the plaques were cleared and normal mental functions returned, often completely. Human trials may begin this year.

With hundreds of millions of lives at stake, and billions of dollars, the search for an Alzheimer’s cure will continue.   TJ  

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