Farr’s work has also demonstrated that antisense is capable of crossing the blood-brain barrier, reducing oxidative stress and neuroinflammatory cytokines, and improving the outflow of overproduced beta-amyloid from the brain. “We really think antisenses have great potential for treating Alzheimer’s disease,” she said. “And we’re moving over now to the tau side.” Farr’s team is hoping to develop an antisense that can bind with glycogen synthase kinase (GSK), one of the proteins involved in the phosphorylation of tau protein. “We’ve found, at least in our mouse models,” she said, “that we can indeed improve learning and memory when we decrease these proteins.”
Rehabilitation Research: Treatments and Therapies
Because there is still so much to learn about the etiology of Alzheimer’s disease, the bulk of VA’s research concerns basic biomedical science. “The research has to mature to a certain point before it can be moved into a clinical setting and studied in the context of a rehabilitation intervention,” said Tshaka Cunningham, Ph.D., scientific program manager for aging and neurodegenerative diseases in VA’s Rehabilitation Research and Development (RR&D) Service.
One of the best examples of research maturing along this trajectory is the work of Dr. Sam Gandy, Ph.D., director of the Center for Cognitive Health and NFL Neurological Care at the Icahn School of Medicine at Mount Sinai, and a physician researcher at the James J. Peters VAMC in the Bronx. A world-renowned expert in the metabolism of beta-amyloid since the 1980s, Gandy several years ago, with funding from VA’s Biomedical Laboratory Research and Development Service, collaborated with Dr. Michelle Ehrlich, a professor of pediatric neurology, genetics and genomic sciences, and pediatrics at Mount Sinai, to develop a breakthrough animal model, a mouse in which brain amyloid aggregated – rather than into the classical plaques – into floating clumps called oligomers.
These clumps, explained Gandy, are misshapen in such a way as to be invisible to existing amyloid imaging technology. “The mice were just as behaviorally impaired as the mice with plaques,” said Gandy. “And this ‘oligomer only’ mouse reinforced the idea that while the plaques themselves may be an obvious thing we can see with the microscope, the real poisons may be these floating clumps that we cannot see.”
This finding, along with several others – today’s imaging tools have demonstrated, for example, that amyloid buildup can begin up to 30 years before the first symptoms of Alzheimer’s emerge – has led Gandy and most researchers to target prevention of the disease, rather than treatment. “Until recently – and probably because we were treating too late – our efforts at reducing amyloid made their brain scans look better, but didn’t help them at all clinically,” he said. “So we’ve long believed if amyloid is going to be the target, then the earlier the better.”
In a study reported in August 2014 in the journal Molecular Psychiatry, Gandy and colleagues reported one of the most promising results yet in an animal model: Mice with amyloid clumps, treated with an experimental drug known as BCI-838, not only showed a reduction in amyloid, but also formed new nerve cells in the hippocampus – the memory center of the brain and one of the first regions of the brain to suffer Alzheimer’s damage. The drug, originally developed to treat depression, raises the possibility that treatment may be possible for patients who are already symptomatic. “Right now,” Gandy said, “we’re working to develop a derivative of this compound that we can use in clinical trials.”
Amyloid accumulation is clearly part of what defines Alzheimer’s pathology, Gandy said, but genetic analyses of typical non-familial Alzheimer’s patients have revealed about two dozen genetic changes common among them – and only a few were obviously related to amyloid metabolism. “Most were either cholesterol-related genes, or inflammation-related genes, or protein-sorting or intracellular trafficking-related genes. So there’s a lot of interest now in the roles of cholesterol and inflammation in Alzheimer’s, for a variety of reasons.”
Early in her investigative career, Sally Frautschy, Ph.D., chief of neurogerontology at the Geriatric Research, Education and Clinical Center (GRECC) at VA’s Greater Los Angeles Health Care System and professor-in-residence in the Department of Neurology at UCLA’s David Geffen School of Medicine, began to focus on the role of inflammation in Alzheimer’s. For the past 20 years she’s been investigating the anti-inflammatory properties of curcumin, a molecule in the turmeric plant known to affect both inflammation and oxidative damage – and, Frautschy has discovered, to enhance the mechanism for removal of toxic tau aggregates from the brain. The knowledge gained from those studies has led to her most recent clinical trial, which she’s conducting in partnership with Dr. Edmond Teng, Ph.D., another VA GRECC and UCLA investigator who also is directing clinical trials at the UCLA Alzheimer’s Center.
The trial combines a regimen of curcumin, molecularly customized to pass through the blood-brain barrier, combined with yoga therapy, and administered to veterans with mild memory loss who may be at risk for developing Alzheimer’s disease. Typically, factors increasing risk for cardiovascular disease, such as insulin resistance and inflammatory dysregulation, present risk factors for mild cognitive impairment (MCI), the early stage of Alzheimer’s disease.
Yoga was chosen as the behavioral component for the trial, Frautschy said, not only because exercise has been shown to reduce the risk for Alzheimer’s, but also because yoga, in particular, involves cognitive and circulatory components that might prove beneficial. Because of their relatively low cost, behavioral interventions for facilitating brain health are receiving significant attention from researchers. One of them is Michael Cole, Ph.D., a research scientist and neuropsychologist in the VA’s Northern California Health Care System and the Alzheimer’s Disease Center at the University of California-Davis. Cole’s work examines neurocognitive rehabilitation approaches – cognitive exercises, compensatory technique training, memory strategies and memory aids – that have proven successful in normal aging, and which have shown some promise in countering symptoms of MCI and mild dementia.
Behavioral therapies have also proven effective in countering the elevation of stress-related hormones such as cortisol, which has been linked to hippocampal injury and associated cognitive decline. Cole, along with co-primary investigator Juliana Baldo, Ph.D., and colleagues at UC-Davis, has designed a series of studies examining the efficacy of an eight-week course on mindfulness-based stress reduction (MBSR). The first course is being taught by a certified instructor – Cole – to patients with mild cognitive complaints that don’t rise to the level of an MCI or Alzheimer’s diagnosis. “Preliminary effects so far,” Baldo said, “seem promising in reducing things like blood pressure, heart rate, and cortisol levels.”
The group is planning future studies of course outcomes among patients with MCI and Alzheimer’s disease. “For those folks, we realize mindfulness training has definitely been shown to be more efficacious for executive functioning and attention, rather than for directly treating memory deficits,” Baldo said. The program for these groups is likely to be a hybrid intervention, combining mindfulness training with memory exercises.
Cole’s mindfulness training evaluation lies near one end of the continuum of VA’s Alzheimer’s research, in which the smallest unit of study is the individual patient. Such a broad spectrum is necessary, said Cunningham, given a topic that has confounded researchers for so long. “The reality of it is that this particular disease condition, Alzheimer’s, is just very intractable, very difficult to treat,” he said. “There is still a lot of etiology that needs to be understood, and we’re discovering new methods for rehabilitation while we’re discovering more about how the disease happens, and how new molecules and compounds might be used in treatment. The story of our Alzheimer’s research isn’t done yet, by any stretch of the imagination.”
This article first appeared in The Year in Veterans Affairs & Military Medicine, 2015-2016 Edition.