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Alzheimer's and Genetics

We’re still a long way from a cure, but researchers are making important breakthroughs in the fights against this frightening disease. (2014)


By Charlotte Huff

Unlike most Americans, Karla Hornstein knows her vulnerability to the brain-robbing disease called Alzheimer’s, specifically a rare and early-onset form that runs in families and has haunted her own.

Her father developed symptoms in his early 40s, decades before genetic testing was available. “We all went on with our lives and had our children and probably didn’t think about it too much,” says Hornstein, a 56-year-old office manager in Fargo, North Dakota, and the mother of two grown children. Then several of her siblings began to suffer memory gaps, difficulties with multitasking, and other symptoms, all beginning in their 40s, first two of her brothers, followed by a sister.

By then, researchers had identified three genetic mutations that can be inherited and, if they are, cause a form of Alzheimer’s called early onset because it strikes before age 65 and sometimes far earlier. Since 2004, Hornstein and all five of her siblings have been tested. Hornstein is the only one who doesn’t carry PSEN1, one of the mutations.

But despite the stress and sadness of watching her siblings fade away from their essential selves, Hornstein takes pride in her extended family’s role in ongoing research that’s reaping insights that might pave the way for treatments — both for early onset and the far more common late-onset form. The research that has involved nearly 20 members of her family already has documented brain changes that can be traced back 15-plus years prior to symptoms. Now the next phase of that study, called the Dominantly Inherited Alzheimer Network Trial, will assess whether two drugs can slow the progression of the disease. One of Hornstein’s brothers will travel this year to Washington University in St. Louis to participate, and at least one of her nieces and nephews will enroll at another research site. “That’s where I put all my hope now,” she says.

To date, Alzheimer’s research has been a heartbreaking journey in frustration for doctors and patients alike. Efforts to slow or thwart symptoms, by targeting an influential protein in the brain called beta-amyloid, have not panned out. But that brick wall has propelled an investigational reboot in recent years, with researchers looking at a raft of other potential cognitive culprits, says Mark Mapstone, an Alzheimer’s researcher at the University of Rochester Medical Center. “I think it’s commonly accepted now that beta-amyloid is necessary for the disease but not sufficient to cause the disease,” he says. “And that’s a critical initial turn in thinking.”

These efforts are being assisted by advances in imaging and other screening techniques that can track key proteins and other biomarkers far earlier in the disease process. Vast registries of genetic data are being collected and sifted through. Researchers also are investigating the role of various assaults that our brains might weather over a lifetime — from concussions to high cholesterol to advancing age. Their two-pronged objective: to develop easier and more affordable tests to catch subtle brain changes long before any of us misplaces the remote control or scrambles our sentences. Then they want to identify medications that can intervene earlier, applying the brakes on that deterioration process.


Brain Assaults: Within and Without

Deciphering what’s happening to the human mind is dauntingly complex to envision, never mind unraveling the massive circuit board involved. Our brains contain 100 billion neurons with information transmitted rapid fire via connections, called synapses, some 100 trillion of them. Given that 5.2 million Americans live with Alzheimer’s, many of us likely have watched and worried as loved ones question whether misplacing names and items is simply evidence of human fallibility or a harbinger of something far more worrisome.

The damage to the brain, initially too subtle to easily detect amid the swirl of daily life, steadily and relentlessly erodes the very neurons that encapsulate who we are and how we function. Some people may live for decades with worsening symptoms. Hornstein’s father, who died in 1989 at age 58, struggled to swallow enough to eat in his final days. Hornstein’s oldest brother has died. Two other siblings live in long-term-care facilities.

Researchers initially focused on beta-amyloid because of the protein’s connection to the three mutations that cause early-onset disease (APP, PSEN1, and PSEN2). Those inheritable mutations, which are responsible for less than 5 percent of all Alzheimer’s cases, have been shown to alter how beta-amyloid is processed by the brain. Over time, the sticky protein builds up outside the brain’s neurons, forming what’s described as amyloid plaques. “I think legitimately that got the scientific community very focused around preventing amyloid aggregation,” says neurologist Bruce Miller, who directs the Memory and Aging Center at the University of California, San Francisco. “Maybe exclusively so,” for a stretch, he says.

“Amyloid proteins, APOE4, and tau all seem to contribute to the development of Alzheimer’s disease and may all have to be targeted individually in order to effectively prevent and halt the condition.”

By 1993, those three early-onset mutations had been identified, as well as one that’s associated with a higher risk of developing late-onset Alzheimer’s. That gene, called apolipoprotein E (APOE), whose link to Alzheimer’s was discovered by Allen Roses and colleagues at Duke University, makes a protein that helps to disseminate cholesterol and other fats in our blood. At least one in four of us carries a variant of that gene called APOE4, and it’s found in roughly 40 percent of people with late-onset Alzheimer’s.

Still, frustrating gaps have persisted in the brain blueprint that researchers have been striving to map out. Some people test positive for APOE4 and yet never develop symptoms, while others develop Alzheimer’s without any detectable APOE4 vulnerability.

Similarly, there are unanswered questions involving what’s dubbed the “amyloid hypothesis,” the theory that the plaque buildup is the primary driver of Alzheimer’s. Autopsies have shown that some people accumulate significant amyloid without showing symptoms. One study using a brain imaging technique called PET (positron emission tomography) has shown, in fact, that one out of five elderly adults (ages 65 to 88) functions fine cognitively, even with detectable amyloid deposits.

More to the point, amyloid-targeting drugs such as bapineuzumab and solanezumab — at least when taken by people with mild to moderate Alzheimer’s — don’t appear to help improve thinking, memory, and other cognitive difficulties, according to the results of Phase 3 studies published earlier this year in the New England Journal of Medicine.

Meanwhile, some researchers have become increasingly intrigued by another brain protein, called tau, first linked in 1998 to a type of dementia called frontotemporal. It’s now believed that an abnormal form of tau can play a destabilizing role by forming tangles within the neurons themselves. In short, while the sticky amyloid plaques appear to damage the neuron from outside, tau can strangle its functioning from within.

The location and number of the tangles appear to correlate with the type and severity of the symptoms, says Bradley Hyman, a neurologist and researcher who directs the Memory Disorders Unit at Boston’s Massachusetts General Hospital. It’s believed that they first develop in a brain region called the entorhinal cortex, he says, considered to be a key staging area for memory coordination. “So it’s no surprise that memory disturbances are the first clinical symptom of Alzheimer’s disease, if the first part of the brain that’s affected has to do with memory,” Hyman says.

Along with amyloid and tau, the APOE gene itself can spin off toxic protein fragments, says neurologist Lennart Mucke, who directs the Gladstone Institute of Neurological Disease in San Francisco. “Those three players — amyloid proteins, APOE4, and tau — all seem to contribute to the development of Alzheimer’s disease,” he says, “and may all have to be targeted individually in order to effectively prevent and halt the condition.”

The list of potential genetic players doesn’t stop there. Researchers are looking at BIN1, CLU, and PICALM, among others. To facilitate such research, officials at the National Institutes of Health last year released complete sequencing data from 89 families with late-onset Alzheimer’s. Federally funded studies are delving into whether other diseases and risk factors, including high blood pressure and diabetes, may strain our brains in ways that leave us more vulnerable. Sports-related concussions also are being scrutinized, UCSF’s Miller says. “I think there is a concern, and I think some good epidemiological studies have supported it, that suggest that brain trauma is a risk factor for Alzheimer’s disease,” he says.

Luckily, our brains appear to be resilient enough to withstand some cognitive assaults, whether genetically or environmentally driven. As one example, Hyman says we can likely cope with some tau tangled within our neurons. “I view that as being the equivalent of: Can you run a marathon even though you have a little arthritis in your knees? Well, there are people who can. Is that [tau buildup] a healthy thing for the brain? Unlikely.”

But these cognitive hits, as they amass over time, gum up and erode connections crucial to humming communication between neurons, Hyman says. “Ultimately, what goes wrong, it seems, is that neurons no longer talk to each other,” he says. “Although it’s too simplistic maybe, it’s clear that the more different ways you disrupt a complicated system [like the brain], the more clinical impact there may be.”


Pulling Back the Curtain

Alzheimer’s has long been understood to have a flu-like incubation period, counted in years rather than days before symptoms start, says Eric McDade, a neurologist at the University of Pittsburgh. But a pivotal early-onset study that McDade was involved with, looking at brain changes in 128 participants, determined that the changes emerged even earlier. By studying the brain itself and the cerebrospinal fluid — the colorless liquid that bathes the brain and spinal cord — researchers identified increases in amyloid and tau proteins dating back 15 years prior to the expected onset of symptoms, according to the 2009 findings.

Studies like these have been made possible by a key advance in PET imaging. To highlight the amyloid, a harmless tracer chemical is injected into the patient’s bloodstream, which then accumulates in the plaque, emitting a fluorescent light that can be picked up by the PET scan. The tracer chemical for amyloid was discovered first, followed later by one to detect tau.

But the amyloid imaging scan can be quite costly, typically running from $3,000 to $7,000 per scan, according to a scientific leader at the Alzheimer’s Association. An easier and more affordable option is needed, and researchers are making some headway.

Earlier this year, a team that included Mapstone at the University of Rochester announced that it had identified a pattern in the blood that — based on relative levels of lipids, or fats — helps to identify those at imminent risk of developing the disease. The blood signature could predict with greater than 90 percent accuracy whether someone would develop mild cognitive impairment or Alzheimer’s disease within the next three years. Mapstone cautions that the predictive approach is not yet a test and will have to be confirmed by other researchers.

In Texas, researchers have been working on an Alzheimer’s test that can be incorporated into a busy family doctor’s practice. Completing even a brief cognitive assessment can consume five minutes, an eternity during time-pressed appointments, says Sid O’Bryant, an Alzheimer’s disease researcher at the University of North Texas Health Science Center in Fort Worth.

O’Bryant’s approach, which analyzes a panel of proteins, can determine with 88 percent accuracy whether someone already has Alzheimer’s. The test, which has been independently validated, also has a false positive rate of 10 to 20 percent, which means that number of people ultimately won’t prove to have the disease. But O’Bryant views the test’s potential as a screening snapshot, similar to how a patient might be sent to a cardiologist after a poor showing on heart-related blood work.

“If your blood profile is out of whack and suggests possible Alzheimer’s or other neurodegenerative diseases, we want that to trigger a referral to a dementia specialty clinic,” he says. “That’s how they will get the full diagnostic workup.”


Earlier Drug Intervention

Long term, the goal is to pair better screening and diagnostic techniques with drugs that work better in that pre-symptomatic stage, including potentially with the amyloid-targeting medications. One study launched this year will again test solanezumab, this time in people considered at high risk for late-onset Alzheimer’s but before any symptoms appear. Those 1,000 participants in the A4Trial (anti-amyloid treatment in asymptomatic Alzheimer’s disease) will only be enrolled if PET images show they have significant amyloid buildup in their brains.

The drug phase of the early-onset DIAN study, which involves a few members of Hornstein’s family, similarly will adopt an earlier-is-better treatment strategy. Researchers will recruit individuals, such as Hornstein’s niece Robin McIntyre, who have a genetic risk but few to no symptoms.

Once effective drugs are found, they likely won’t be dispensed as one-size-fits-all, but rather based on an individual’s genetic profile and how far the disease has advanced.

McIntyre’s mother has Alzheimer’s, but McIntyre hasn’t experienced any symptoms and would rather not know if she carries the PSEN1 mutation that has changed her family’s life. (See sidebar: Why Learn Your Genetic Risk?) But the study investigators will. The two-year study is designed so those who test positive can count on a 75 percent chance of getting one of the two amyloid-targeting drugs (gantenerumab and solanezumab) instead of a placebo (sugar pill). McIntyre, a 31-year-old hairstylist in Laramie, Wyoming, remains hopeful for the future promise of these and other drugs.

“At this point,” she says, “the thing that bothers me the most is that all of this [drug research] didn’t happen in time to save my mom.”

Once effective drugs are found, they likely won’t be dispensed as one-size-fits-all, but rather based on an individual’s genetic profile and how far the disease has advanced, says Dean Hartley, who directs science initiatives, medical, and scientific relations at the Alzheimer’s Association. Consider how one patient at risk for heart disease takes a single cholesterol medication while another might swallow a cocktail of drugs after surviving a heart attack, he says.

“It’s highly likely that as you develop Alzheimer’s disease, the [drug] targets might change,” he says. “Or you may need combination therapies in order to protect against the later stages of mild to moderate Alzheimer’s, when there are multiple things going wrong in the brain at that time.”


Vaccine Potential?

The long shot, the cognitive holy grail, so to speak, would be if researchers could develop a vaccine that would stimulate the immune system to combat the disease. That’s the goal that daily drives Roger Rosenberg as he works in his National Institutes of Health-funded Alzheimer’s Disease Center at the University of Texas Southwestern Medical Center in Dallas. “I decided 10 years ago that I would go for high-risk, high-potential gain to come up with some kind of therapy,” he says.

Efforts by other researchers to develop a vaccine were derailed in 2002, when an early-phase research study involving an immune-system stimulating drug — dubbed the Alzheimer vaccine — was halted by federal officials. The drug, called AN-1792, was supposed to encourage the immune system to recognize and attack damaging amyloid plaque, and it had been demonstrated to do so in mice. But 6 percent of the participants in the human clinical trial, all of whom had Alzheimer’s, developed swelling in the brain.

However, there were still some encouraging signs, Rosenberg says. Autopsies of eight vaccine recipients who later died from other causes showed that while their dementia had worsened, their brains contained far less amyloid plaque compared with those who didn’t receive the vaccine.

Rosenberg’s ambition: to create a vaccine that would prompt the immune system to attack the plaque without also triggering a harmful inflammatory reaction. He has been testing an alternate approach in which the DNA that codes for the beta-amyloid sits on tiny gold particles, which are then propelled by a pressure gun into the skin. Although the DNA results in the creation of the beta-amyloid protein, which in turn leads to the production of amyloid antibodies, Rosenberg’s reasoning has been that this more indirect approach won’t trigger a harmful inflammatory response.

The vaccine has been studied only in animals, but two studies involving mice have shown that the approach reduces amyloid plaque by roughly half, Rosenberg says. And there has been no inflammatory response detected.

Rosenberg would like to have the vaccine ready for human trials about the same time that drug trials like A4 and DIAN demonstrate the brain benefit of tackling plaque earlier in the disease process. That opens the door for a vaccine approach, which Rosenberg argues would be easier to administer across large groups of at-risk adults.

Like others pushing for better answers, the 75-year-old neurologist feels the pressures of passing time, as patients and their families continue to suffer and the baby boomers age into their later decades. By 2050, the number of annual cases of Alzheimer’s is projected to double. “Alzheimer’s is a horrific disease,” Rosenberg says. “The argument is that if we could do that in patients, reduce it [the amyloid buildup] by half, you could delay the onset of the disease by five years.”