New Research on Understanding Alzheimer’s

Not all of Dr. Richard Mayeux’s elderly patients have Alzheimer’s disease; not all will even go on to develop it. Most of them are still leading full, healthy lives, interacting with their families and contributing to their communities. But Mayeux, an Alzheimer’s researcher and physician at Columbia University, asks them all anyway: Will they help him in his war against the disease? It’s been a long and disappointing campaign so far. Alzheimer’s disease — the degenerative brain condition that is not content to kill its victims without first snuffing out their essence — has for decades simply laughed at such efforts.

More than 5 million Americans currently suffer from Alzheimer’s disease, a number that will grow to 13.4 million by 2050. There is no cure. The therapies that exist — drugs and lifestyle behaviors such as keeping the mind sharp with enriching social relationships and stimulating the brain with games and puzzles — can only delay, not stop, the onset of memory loss, confusion and cognitive decline that generally extend over a period of several years or, more often, decades. There isn’t even a definitive test for Alzheimer’s.

Mayeux knows that defeating Alzheimer’s means first recruiting volunteers to join a study that can help identify who is at greatest risk of developing the condition. The results could paint a clearer picture of the factors that put people in danger. A disease that gives up clues to those factors is one that has revealed its weak spots — and that, perhaps, can lead to better treatments. Mayeux deeply believes this, and that’s what he tells his patients, but still, they take some convincing. Said one prospective participant: “The way I see it, even if you predict when I will get Alzheimer’s, you haven’t got anything that I can do for it.”

The patient has a point. Who in his right mind would want to know he had a disease that would inevitably rob him of that mind? But a lot of us may eventually find ourselves slipping away in that sad fashion. Health experts estimate that a 65-year-old has a 10% risk of developing Alzheimer’s and that baby boomers currently approaching peak age for the disease (60 to 80) will add $627 billion in Alzheimer’s-related health care costs to Medicare. There is a considerable psychological price tag too, for patients and caregivers alike — and a fear factor. In a recent poll conducted for The Shriver Report: A Woman’s Nation Takes On Alzheimer’s, 84% of adults surveyed were concerned that they or someone in their family would be affected by the disease.

That fear is compounded by the belief that research for Alzheimer’s is lagging behind that for other diseases. While 81% of those polled saw great progress being made in curing heart disease and 74% said the same for cancer, only 48% felt researchers were making strides against Alzheimer’s. Money is partly why. “We spend $5.6 billion a year funding cancer studies, $1 billion a year for heart disease … and $500 million to study Alzheimer’s,” says Dr. Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center. “Yet what is going to get most of us in the next few years is Alzheimer’s.”

Over time, the feeling has taken hold that beating Alzheimer’s is the cold fusion of medical research: everyone agrees it would be great, and everyone who tries it fails. And yet maybe, just maybe, that’s changing. For the first time since the disease was identified more than a century ago, doctors are closer to uncovering its secrets. Alzheimer’s, like all other degenerative ills, is driven by genes, and in the past year, scientists have come up with a suite of relevant ones. The disease is thought to be caused by a buildup of protein-based plaques in the brain, and investigators now believe they have an understanding of possible ways to interrupt that process. Technology is helping too, as researchers exploit new ways to scan the brain and detect the first signs of trouble, peering deeper into human and animal neural tissue to pinpoint the very molecules that give rise to the disease.

“Our understanding of Alzheimer’s is better than it looks based on the clinical trials,” says Lennart Mucke, director of the Gladstone Institute for Neurological Diseases and a neurologist at the University of California, San Francisco (UCSF). “Despite all the reports about how dismal the situation is, it is probably more hopeful in some respects now because there are more candidate [treatments] in the pipeline.”

Treatments and hope are the two things people are looking for most, and if you’ve listened to Alzheimer’s experts over the years, you haven’t heard them speak much about either. They are doing so now — cautiously, tentatively, promising nothing yet, but the change is real. And the reason is the research.

Starting Early
If even the most optimistic scientists are still talking only warily about progress, it’s no wonder. The Alzheimer’s field has until now been a graveyard of hope. In 2002 a promising vaccine caused dangerous inflammation in the brain and spinal column and had to be abandoned after years of research; last August, a highly anticipated drug worsened rather than improved cognitive symptoms.

The fact that optimism does exist comes mostly from scientists’ ability to apply two important lessons learned from the disappointments of the past. The first involves timing. Experts are now convinced that it’s crucial to treat Alzheimer’s patients as early as possible, perhaps even before they show signs of memory loss or cognitive decline, rather than attempt to improve a brain already scourged by the disease. The second involves the scope of the medical assault: adopting a multipronged approach that addresses as many of the disease’s complex abnormalities as possible may improve the chances that new therapies used early on will not only delay symptoms but also reverse them.

Shifting the focus to the earliest stages of the disease wasn’t as obvious as it seems in hindsight. Cognitive decline is a natural consequence of aging, and confusion and memory loss are often just inconvenient parts of getting older. It was understandable, then, that doctors were reluctant to introduce more uncertainty by attempting to tease apart Alzheimer’s dementia from the so-called senior moments typical of normal aging.

So rather than make the attempt, they focused on the most obvious target: the buildup of a protein called amyloid in the brains of Alzheimer’s patients. While amyloid in living patients can be detected with a spinal tap, its presence doesn’t necessarily indicate the disease; it’s the accumulation of the protein into plaques, which also include cellular debris like dead and dying neurons, that is linked to the disease’s symptoms. A definitive Alzheimer’s diagnosis is thus possible only after the patient’s death, when an autopsy of brain tissue can verify the hallmark lesions. Initially it made sense for researchers and drugmakers to focus on finding ways to shrink plaque buildup and reduce the amyloid burden in the brain. That, surely, would lead to improvement.

But to date, these well-intentioned efforts have been fraught with failure and riddled with side effects. The agents that target amyloid plaques affect other processes in the body too, including those that regulate how cells communicate as well as the development of heart, pancreas and immune-system cells. What’s more, it’s not even clear that getting rid of the plaques has any effect on brain function at all. When scientists analyzed the autopsied brains of patients in the failed vaccine trial, for example, they noted that the subjects had fewer plaques than before they received the vaccine but still had shown no improvement on tests of mental function. To confuse matters more, in tests involving animals with the equivalent of Alzheimer’s, mice whose brains were loaded with amyloid performed as well as those without the plaques. When so self-evident an A does not lead neatly to a B, science gets awfully flummoxed.

There were several explanations for the seemingly conflicting results, all of which meant that the researchers might unfortunately have steered their work too heavily in one direction. Perhaps amyloid was not a critical contributor to the disease at all but a red herring, and something else was driving the death of neurons. Or perhaps amyloid was a factor in the pathology but only one of many. It was also possible that amyloid was indeed pushing the disease but that the vaccine and drugs used to dissolve the plaques were introduced too late and in too small a dose. Many of those drugs were designed to block the breakdown of amyloid into smaller fragments, which have a greater tendency to clump together. “By the time a person is impaired to the point of dementia, there is probably sufficient damage done to the brain that we really can’t reverse it,” says the Mayo Clinic’s Petersen. “It has gone too far.”

If that’s the case, then testing the drugs on patients whose brains are just beginning to accumulate amyloid might yield more success. But finding such patients, many of whom show no signs of memory loss or decline in mental function, is a challenge. So in 2004, the National Institute on Aging (NIA), part of the National Institutes of Health, partnered with pharmaceutical companies to create the Alzheimer’s Disease Neuroimaging Initiative, a $60 million project tasked with identifying easily detectable differences — preferably through blood tests or brain scans — between Alzheimer’s patients and unaffected individuals. It was nuts-and-bolts science, unglamorous but essential, and it wound up attracting 600 patients who either already suffered from symptoms of Alzheimer’s dementia or had mild cognitive impairment — a preliminary stage of the disease — as well as 200 cognitively normal control-group volunteers.

Already the program has isolated a few dozen intriguing protein markers in blood and spinal fluid that may herald Alzheimer’s disease and could help researchers identify high-risk individuals before symptoms set in. Also, newer, better brain scans are helping detect the amyloid patterns that previously could be verified only by autopsy. Being able to say, “This patient appears to have Alzheimer’s” — as opposed to, “This deceased patient had Alzheimer’s” — is no small thing. Still, as with the blood and spinal-fluid tests, the challenge remains to understand the link between the plaques and the actual symptoms. What is the threshold between normal and diseased states?

For those answers, scientists need to test the measures on at-risk, asymptomatic populations. And for that, they need a consistent way to identify those populations, even if nothing is available to treat them. That’s why in July, the NIA and the Alzheimer’s Association decided to update their criteria for helping doctors diagnose Alzheimer’s by defining three distinct patient groups: those who are symptom-free but at high risk, those with mild cognitive impairment and those with Alzheimer’s dementia. The guidelines fold in the latest understanding of how brain scans and other tests can help distinguish among the three groups and perhaps even specify which treatments among the many being explored might be most effective at each stage of the disease.

Because Alzheimer’s cannot be absolutely, definitively diagnosed until death, patients are currently given a probable diagnosis based on their performance on memory and recall tests and reports from family members. The blood and spinal-fluid tests, along with the brain scans, could improve the predictive accuracy of these measures. But Mayeux is still wary. “While everyone acknowledges that the [markers] are useful,” he says, “there isn’t yet a standard test that everybody agrees means the same thing when they see a score.”

Still, the early data look promising, suggesting the screens may be 80% to 90% accurate in picking up the earliest signs of the disease. This has more than simply diagnostic value; it also allows researchers to start targeting candidate medications and be more confident that the patients who receive them will benefit. “Getting early diagnoses will have an important impact on the way we design trials and possibly even the rate at which we complete those trials and come up with effective treatments,” says Dr. William Thies, medical director of the Alzheimer’s Association. For example, coupling screening tests with treatment could cut a 65-year-old’s lifetime risk of developing Alzheimer’s in half.

Widening the Approach
But that can’t happen, says UCSF’s Mucke, unless scientists start designing smarter therapies. It’s clear that concentrating on amyloid alone is not sufficient to reverse Alzheimer’s, so investigators are working hard to identify additional targets. Among the potential areas of interest are genes like apolipoprotein E (ApoE), which in certain forms can promote the formation of amyloid. Also attracting interest is a neural protein known as tau, which stabilizes axons, the long extensions that nerve cells send out like highways to communicate with one another and reach faraway tissues like muscles in the fingers and toes.

Researchers now have a better idea of how all of these components come together in the deadly cascade that leads to Alzheimer’s. The disease begins, they believe, when for still unknown genetic and other reasons, the brain starts to churn out amyloid. Initially the amyloid appears as a long protein that is then cut by enzymes into shorter fragments that become molecularly sticky and clump together, forming a plaque. Once the plaques form, tau proteins that maintain the structural integrity of the neural highway break down, leaving the equivalent of potholes that interrupt the electrical signals traveling along the nerve. With this communication flow disrupted, nerve cells start to wither and die, leaving behind their tangled remains. That in turn activates the immune system’s inflammatory response, which attempts to remove the debris.

The result is a brain full of dead and dying neurons, and the shutdown of neural connections leads to a drop in cognitive function. Targeting each of these players — inhibiting ApoE’s effect on amyloid production, controlling the formation of amyloid fragments and limiting tau’s breakdown of nerve connections — may be necessary to control the resulting mess. “We have many leads for potential treatment targets,” says Mucke. “But the difficult thing is to know what the relative impact of each is on the human condition. And we won’t know this until we have found drugs that can block each of them or combinations of them, to see how much improvement results.”

Seeing that benefit in the mental function of those at risk for Alzheimer’s disease will be the ultimate test for this new strategy. But even if therapies are years or decades away, identifying patients earlier in the disease cycle will remain valuable. By knowing they are at risk for Alzheimer’s, patients can plan better for the future and make changes to their lifestyle, such as exercising and staying mentally and socially engaged — behaviors known to delay the onset of symptoms.

It is a complete person who typically receives a diagnosis of Alzheimer’s; it’s the wreckage of that person that is ultimately killed by the disease. But before that happens, the complete person has power. Those who build a deeper reserve of neural function by staying cognitively active remain fit longer. That means living robustly and well is one of the best weapons we have against the disease — at least until science’s heavier artillery is finally ready to be wheeled into place.

This article originally appeared in the October 25, 2010 issue of TIME.