Alzheimer’s: Untangling the Research

First came the discovery of beta-amyloid plaque as a precursor of cognitive decline, and then came the tangles of tau and wonderment in researchers’ minds as to their relationship. A complete picture of the pathophysiology of Alzheimer’s continued to elude the medical community—until now. Take a look at the research that has closed longstanding knowledge gaps, what it means for dawning drug approvals and what other options are still in the works.

Several genetic, diagnostic and therapeutic breakthroughs have been presented during the course of the year, most especially during the Alzheimer’s Association International Conference (AAIC) in Copenhagen in July. These have provided nuance to our understanding of not only how the disease develops and progresses, but how, in time, researchers could come to treat it.

On another level, the international community’s growing awareness of the impact of Alzheimer’s appears to be teasing out more funding, smoothing the way toward regulatory approval of investigational drugs and applying gentle pressure on governments and private payers to reimburse for medical care that could significantly improve patients’ quality of life as well as physicians’ clinical certainty.

The nature of their relationship

This fall marked the publishing of the first 3D neuronal model demonstrating the interaction and pathophysiology between beta-amyloid plaque build-up and tau aggregation.

Researchers at Massachusetts General Hospital in Boston found that by amplifying the effect of Familial Alzheimer’s Disease (FAD) mutations in a stem-cell based culture of potent beta-amyloid precursor protein and presenilin1 protein—colloquially known as Alzheimer’s disease in a dish—they were able to induce a substantial amount of amyloid deposition in a human neuronal model. The 3D cellular model exemplified all the classic signs of Alzheimer’s pathology: filaments of tau and phosphorylated tau that was detergent-resistant and silver-positive seemingly wrapped up in a bow in both the soma and neuritis as seen by fluorescence microscopy. Additionally, researchers evaluated the feasibility of b- and c- secretase inhibitors as anti-amyloid therapeutics and found that they depressed amyloid as well as tau pathology.

The study proves that amyloid is the key to tau aggregation, and the discovery marks a major improvement in not only our grasp of Alzheimer’s disease but it also clears the way forward for validating next-generation drugs and imaging agents.

In another Massachusetts General study published in JAMA Neurology in September, researchers were able to track the synergistic effect of amyloid and neurodegeneration in the brains of clinically healthy people over time. The study included 166 subjects with no sign of dementia or neurodegenerative disease. Of these, 92 were women and the overall average age was 72. Pittsburgh Compound B-PET was used to determine longitudinal amyloid pathology. Researchers also tracked hippocampus volume with MR imaging and glucose metabolism with FDG-PET. Cognitive tests were performed on an annual basis and subjects were placed in Alzheimer’s staging categories, including beta-amyloid negative stage 0, beta-amyloid positive but no major neurodegeneration in stage 1, beta-amyloid and neurodegeneration in stage 2, and full-on Alzheimer’s pathology in the final stage.

Results of the study showed that after a mean 2.09-year follow-up, 59.6 percent of beta-amyloid positive subjects showed signs of neurodegeneration—they were significantly more likely to than other subjects. Cognitive decline was only seen in people who had both beta-amyloid deposition and signs of neurodegeneration. The researchers were able to ascertain that the adverse synergy of the two caused greater decline than the individual impact of the two when combined. This provides clear evidence that preventative measures and potential therapies will need to address both parts of the pathology (JAMA Neuro. 2014 Sept 15).

The role of TDP-43

This year’s AAIC held in Copenhagen, Denmark, in July ushered in several pivotal studies, including one presenting a new protein implicated in Alzheimer’s pathology and other neurodegenerative diseases. The Alzheimer’s Association held a press briefing featuring Ralph Nixon, PhD, chair of the Alzheimer's Association Medical and Scientific Advisory Council. Nixon provided some context for the protein, officially known as TAR DNA binding protein of 43kDa (TDP-43). Preliminary investigation suggests that the protein could be a missing link in a triangle with beta-amyloid and tau, with all three leading to neuro-toxicity. Researchers are still working to find out how TDP-43 fits into the current schema of diagnosis and investigational treatment.

“We know that Alzheimer’s is a multifactorial disorder and we don’t know some of the factors that I think are going to be key to the ultimate treatment,” Nixon explains. “We heard about one additional protein factor that had been recognized in several other neurodegenerative diseases perhaps a part of the mechanism found in Alzheimer’s disease in certain brain cells and, more importantly, its association with the worsening of memory and also with more rapid progression of brain shrinkage in the specific area that is related to memory—the hippocampus.”

In this study, researchers at the Mayo Clinic in Rochester, Minn., tested TDP-43 to see if it had an impact on memory and cognition independent of the pathology of tau and amyloid. Results of the study confirmed a correlation between cognitive decline and loss of memory and amounts of localized TDP-43. Researchers were able to verify this link from autopsy data of 342 subjects who had undergone significant cognitive testing and had received Alzheimer's diagnoses clinched by tau deposition in the cortices.

Dean M. Hartley, PhD, director of science initiatives, medical and scientific relations for the Alzheimer’s Association, says that there is more focus on tau right now due to its apparent ability to gauge progression of disease.

“We are pushing very hard on tau imaging because with tau, along with amyloid, we get a better picture of what’s going on in terms of developing Alzheimer’s,” says Hartley. Still, TDP-43 may level up in the hierarchy of clinical interest much like amyloid and tau have in recent years. “It is one more piece of the puzzle for us to understand the disease. Will all people with Alzheimer’s diseases be affected [by TDP-43]? There are a lot of combinations of factors involved that are under investigation. Maybe it is tau, amyloid and TDP-43; maybe it is tau, amyloid and vascular disease. We don’t yet know.”

Taking tau to task

“Tau is something more downstream than amyloid,” explains Philip Scheltens, MD, PhD, director of the department of neurology and Alzheimer’s at VU University in Amsterdam, The Netherlands. This alone sets tau apart from amyloid. Tau seems to be making waves due to its link to ongoing pathology, whereas amyloid may level off as patients’ conditions worsen.

Yet another Massachusetts General study that was presented during the 2014 AAIC is the largest of its kind assessing a novel tau imaging biomarker. Researchers assessed whether tau formation was related to memory decline in 56 healthy adults with a median age of 72. All subjects had undergone three separate memory tests during the course of three years and then were imaged with the tau-imaging agent F-18 T807. Results of the study showed that higher levels of tau were, in fact, associated with declining memory and specifically in the entorhinal cortex and temporal neocortex. This is just one promising trial looking at new agents for dementia.

“It will be very interesting and even intriguing to see if tau imaging will help differentiate different neurodegenerative diseases,” says Scheltens. An important thing to remember is that tau is associated with other diseases, too, including frontotemporal dementia and Parkinson’s. As for tau-based therapies, it will probably be awhile before such a treatment can be fully validated.

“The concept of tau therapy is very interesting, but there have been very few trials done with tau at this point,” says Marc Wortmann, executive director of Alzheimer’s Disease International in London.

However, a few possibilities presented in Copenhagen include a liposome-based vaccine developed in Lausanne, Switzerland; another vaccine is being developed in Bratislava, Slovak Republic. The latter targets the misfolding of tau, which is implicated in the production of neurotoxic aggregates. Preclinical studies have led to encouraging attenuation of tau pathology.

F-18 Flute fine-tunes dementia management

With all this tau talk, let’s not forget about amyloid imaging. It has been a good year for F-18 flutemetamol (Vizamyl). “PiB is the mother of all the ligands,” says Scheltens, and his facility has the on-site cyclotron to produce C-11, but for other facilities who don’t have the infrastructure for such a short half-life, there is F-18 Flute. “F-18 flutemetamol really resembles PiB when you look at the images,” explains Scheltens.

After receiving FDA approval in October 2013, Vizamyl went on to garner European Commission approval at the beginning of September this year. A couple of studies have strongly validated the agent, including one presented during the AAIC that showed how imaging with Flute led to a change in management for 20 percent of patients. This kind of data could go a long way in the current era of coverage with evidence development.

In another study presented at the meeting, patients with mild cognitive impairment (MCI) whose scans were positive for flutemetamol were 2.5 times more likely to progress to Alzheimer's disease. David A. Wolk, MD, associate professor of neurology and assistant director of the Penn Memory Center and University of Pennsylvania Health System, and colleagues conducted the study.

“Our data, similar to other trials which have examined the potential role of beta amyloid in MCI, indicate that such studies may help in stratifying the risk for development of dementia in this population,” according to Wolk. “This prognostic information may have clinical value for patients and families, but will obviously become of much greater significance with the emergence of disease-modifying agents in earlier stages of disease."

Displacing molecular imaging?

A lot of time, money and resources have been dedicated to amyloid and tau imaging and the potential of molecular imaging for the diagnosis of Alzheimer’s. However, a number of investigative diagnostic tests go a completely different—and cheaper—route. There are potential blood tests, eye tests and olfactory tests in development, all of which promise a simple and inexpensive diagnostic solution for Alzheimer’s disease. Such potential has piqued the interest—and apprehension—of the molecular imaging community, but a few things appear to be certain: the accuracy of these tests is not yet high enough to displace molecular imaging, nor were these alternatives ever meant to.

Hartley says the eye test is being developed as a kind of window into the brain to see subtle changes in early onset Alzheimer’s disease.

“These are very simple and inexpensive tests and one of the reasons why we are highlighting them is because they could be done with a physical or an eye exam and relatively quickly,” explains Hartley. “They are not the end-all-be-all for diagnosing Alzheimer’s disease, but they are very good at giving you a baseline for seeing those changes.”

The smell test is a sort of scratch-and-sniff affair. Subjects are asked to smell samples and then describe those odors. This could be helpful because neurodegeneration takes out certain smells very early on in the process of developing Alzheimer’s, says Hartley.

“These may not be as specific as amyloid imaging,” he continues, but if a sign of Alzheimer’s is found with one of these preliminary tests, it should begin a cascade of neurological and clinical evaluations, which may or may not include molecular imaging.

The difference between these kinds of tests and molecular imaging is that the former can capture changes very early in the game, whereas the later is being used to rule out amyloid pathology for definitive diagnosis. These and other alternative tests are still in the research phase and need more clinical trials in larger and more diverse populations.

“I don’t know if there will be a blood test that will be thoroughly accurate,” says Wortmann. “There is one out there from the U.K. that is only 85 to 87 percent accurate, but that is not enough for day-to-day practice. In this case, we still need advanced tests like molecular imaging. ”

No matter how you seek to detect it, one thing is for certain. People need to be diagnosed earlier. “If we could develop a blood test that is almost 100 percent accurate, that would be the holy grail of diagnosis, but I don’t expect that to happen soon,” remarks Wortmann. 

At the time of this magazine’s printing, a study out of Melbourne University was published in Molecular Psychiatry about such a blood test, which screens for specific genetic signatures in microRNA and that was measured to be about 91 percent accurate in 100 subjects with an average age of 80. The accuracy of these kinds of exams can only be improved upon over time. Testing of cerebral spinal fluid (CSF) may be valuable for gaining clinical information. Scheltens advocates the practice at his center where he conducts lumbar punctures for analysis.

Most would want to know

Another notable happening this year was the publication of a large, international survey that suggested three out of four people would want to know if they had an incurable neurological condition. More than 80 percent of respondees said that they would want to know if a loved one was developing such a disease and 94 percent of all those surveyed said they think screening should be covered.

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“Just because there is no cure does not mean there should not be diagnosis,” says Wortmann. “There is still benefit in diagnosing Alzheimer’s disease. All of this knowledge has an impact on the patient. It gives he or she a chance to plan for the future. I think that is important. It is not going to be easy.” There are some studies suggesting that when people are not diagnosed or misdiagnosed—their health outcomes are more precarious and some may even dwell twice as long in the hospital.

The spectrum of responses to questions related to having a neurological disorder and being diagnosed were widespread. People in Europe tended to be more conservative and opt out of knowing whether or not a disorder was present. Brazilian responders were the most apt to want to know (91 percent), whereas people from China (53 percent) were the least likely to want to know.

Climate of approval and reimbursement

The Centers for Medicaid & Medicare Services (CMS) currently covers a limited number of amyloid PET scans as coverage with evidence development. New clinical evaluation showing clear benefits of imaging is now even more crucial, and not just in the U.S. Even when the European Commission approves drugs, each individual country still needs to step up and decide what that country’s level of coverage and payout will be.

“All three amyloid agents are now licensed in Europe and each country by itself will decide whether they should accept this as a commercial product in their country and what the reimbursement scheme will be,” says Scheltens. “This is, of course, a big challenge. I can’t speculate how it will end up, but I can imagine that some countries will make a choice to go with one of the three ligands for full or partial reimbursement. That is really an issue in Europe. Countries are very different.”

More than 44 million people globally were estimated to have dementia in 2013, and that number is projected to more than triple by 2050, according to current world data from Alzheimer’s Disease International.

Another recent survey from AgingCare.com suggests that a significant number of caregivers spend as much as $4,000 or more for Alzheimer's care every month. As the single most expensive health problem in the world, says Hartley, we will eventually have to get it together and loosen more purse strings to fund research studies.

“The value of Alzheimer’s research is in direct relation to the amount of funding we put into it.”    

Now that we have a model of Alzheimer’s pathophysiology that shows us how amyloid and tau work in tandem, and now that we have a better understanding of the demographics of disease and the attitudes surrounding dementia, world leaders, researchers and physicians can come together to improve both diagnostic solutions—imaging and otherwise—to find the best and most appropriate means of detecting and treating this and other devastating neurodegenerative diseases. It won’t be easy, but all the kinks can and most likely will be worked out in time.