In the trenches of Alzheimer research, the battle continues . . . but where do we stand? Is the war on AD dementia nearing conclusion, or are we simply in the initial throes of the fight? Three experts weigh in.
It’s hard to believe that 40 years ago it was proposed that Alzheimer disease (AD) is caused by brain aluminum. Some people even threw out their cookware, in fear of acquiring the memory-impairing disease. The aluminum hypothesis has long since been discounted, and research has marched forward: Î²-amyloid (AÎ²) protein was identified in 1984 in brain plaques of patients with AD, and hyperphosphorylated Ï protein was identified in 1986.1,2 These are true AD markers; possible culprits behind neuronal death and memory impairment.
Amyloid precursor protein (APP) is the larger protein from which toxic AÎ² is made. The APP gene was found on chromosome 21 in 1987, with another risk gene, APOE4, identified in 1993.3,4 In the late 1990s, the enzymes Î²-secretase-1 (BACE1) and Î³-secretase were proposed as enzymes that prune APP, with the deadly effect of creating AÎ² as a brain-cell killer.5,6 Possible ammunition appeared with the discovery of each new AD target.
In the trenches of Alzheimer research, the battle continues . . . but where do we stand? Is the war on AD dementia nearing conclusion, or are we simply in the initial throes of the fight? In interviews with Psychiatric Times, 3 AD experts, Murali Doraiswamy, MD, of Duke Medicine; James Lah, MD, PhD, of Emory University; and Dagmar Ringe, PhD, of Brandeis University weighed in on this important topic.
Today’s AD treatments
According to Doraiswamy and colleagues,7 we now have treatments that target brain neurotransmitters affected by AD. They increase acetylcholine (galantamine, rivastigmine, and donepezil) or block glutamate (memantine). This stalls AD symptoms somewhat, but the disease presses onward. Dr Doraiswamy stated, “there are 4 FDA-approved symptom-relieving therapies that have a modest benefit on cognitive decline. Some of these medications can be used in combination, which may offer some additional benefit over monotherapy. Some people believe that these drugs may also reduce caregiving time and delay institutionalization. The good news is that many of these drugs are now generic and not as expensive as they once were. Unfortunately there has been no new FDA-approved therapy in over 10 years!”
Dr Lah concurred, stating that “current treatments are pretty limited to modestly effective symptomatic medications.”
Drs Doraiswamy, Ringe, and Lah generally agree that it is important to treat AD in its early stages, even before the disease has developed if possible. Much current AD treatment research focuses on this goal.
According to Ringe, “At the moment there is no treatment for AD, and it’s unclear that there ever will be. We are not looking for a treatment once it has progressed. What we are looking for is a treatment for potential AD patients.”
Doraiswamy agreed, stating, “every prevention trial to date has failed and through them we know a lot more about what doesn’t work. And we have made considerable progress in identifying people at greatest risk as well as the possible timeline for brain changes. So we have a much better chemical road map of what goes wrong in the brain than we did a decade ago. From this has come a sense that we need to begin trials a lot sooner-before people develop full-fledged dementia-to give the drugs the best chance to work.”
Problems have appeared with many clinical trials, starting with the Î²-amyloid vaccine. Mouse AD models offered initial promise, since vaccinated transgenic animals showed improved learning and memory, and brain AÎ² declined.8 Unfortunately, human vaccine trials ended because of safety concerns.9
Lah said, “We know that the most serious side effect for anti-amyloid medications is the possibility of brain swelling. In 2000 this was responsible for the termination of the first vaccine trial.”
Despite initial safety concerns, the development of amyloid vac-cines continues under rigorous safety monitoring. For example, UB-311 passed phase 1 trials and continues to be developed as a vaccine by United Biomedical, Inc.10 Initial studies showed improved brain function in a small group of persons with mild AD.11 CAD106 is an anti–Î²-amyloid vaccine co-developed by Novartis and Cytos. An early study indicated that it is safe and produces antibodies, but additional trials are needed to show efficacy in AD.12
Lah discussed the development of other anti-amyloid strategies, specifically monoclonal antibodies. These drugs are delivered intravenously every few weeks. Bapineuzumab did not meet clinical trial primary end points, and is not being pursued further.13 Solanezumab failed phase 3 trials14; however, Lah explained that it “showed more promise in post hoc analyses . . . may have a beneficial effect in patients in the trial with earlier-stage disease.” Therefore, it is being further studied in a prevention trial that will identify susceptible individuals based on genetic markers and brain imaging. He was optimistic about the amyloid antibodies because “there is a lot of hope that when applied earlier . . . they will in fact have a disease-modifying effect.”
Î²- and Î³-secretase inhibitors
In addition to the anti-AÎ² efforts that continue, other approaches focus on the additional AD targets. These include medications that affect the enzymes that are required to produce and release the AÎ² peptides: Î³-secretase and BACE1. Î³-Secretase inhibitor trials have failed thus far; Î³-secretase inhibitors seem unable to lower AÎ² levels when tested in humans. This may have to do with an inability of these medications to enter the brain from the bloodstream.15
BACE1 inhibitors, however, still hold promise. The Merck BACE1 inhibitor, MK-8931, met safety requirements in a phase 2/3 EPOCH study that included individuals with mild to moderate AD. Merck has therefore started a phase 3 APECS trial that will test MK-8931 in people with early-stage AD.16 There has been some concern that BACE1 generally affects other targets, not just the AÎ² protein, which could cause problems with adverse effects and safety. The advancement of MK-8931 to phase 3 is a major accomplishment.
Hyperphosphorylated Ï is another target for AD treatment. Lah stated, “there’s been some preclinical work suggesting that the Ï approach may be effective as well.” In pre-clinical trials, the anti-Ï drug epothilone D seemed to reduce neuronal death, AD-like cellular effects, and cognitive problems in mice.17 This medication prevents the destabilization of neuron microtubules, which is an effect of hyperphosphorylated Ï. The drug is now in phase 1 clinical trials. Other epothilones are being studied for AD as well.18
Increasing nerve growth factor
Therapies that focus on increasing nerve growth factor (NGF), a molecule that can protect brain cells, hold promise. CERE-110 is a surgically implanted noninfectious viral system that injects NGF DNA into the brain.19 The idea is to increase the production of protective NGF. Surgeons implant CERE-110 into the nucleus basalis of Meynert, an acetylcholine-producing brain region that degenerates in AD. Findings from phase 1 trials indicate that CERE-110 is well tolerated.20 This approach is currently being tested in a phase 2 trial consisting of about 50 patients with AD. Half of the participants have received CERE-110 while the other half received a mock surgery. Study results are expected in 2015.
Doraiswamy described other treatment approaches: “There are some new strategies being studied, such as nicotinic neurotransmitter modulation, induced stem cell therapies, RNA interference therapy, brain stimulation devices (eg, direct current stimulation, deep brain stimulation) and metabolism-based therapies.” The effects of aerobic exercise and diet are also being studied; for example, the Exercise and NutritionaL Interventions for coGnitive and cardiovascular HealTh ENhancement (ENLIGHTEN) clinical trial at Duke Medicine is looking at these interventions in people with mild cognitive impairment.21
Retromer science: a new target for AD therapeutics?
An exciting study, recently published in the journal Nature Chemical Biology, looked at pharmacological compounds that bind the retromer complex.22 Retromer moves proteins, including APP, from cellular compartments (endosomes) to the Golgi apparatus for processing. It has been suggested that retromer-associated proteins cause APP and the enzyme BACE1 to stay in the endosome, where BACE1 cuts APP, causing AÎ² to form. Inhibiting this process could prevent AD. By increasing retromer levels and bolstering normal processing, less AÎ² may form.
When the researchers tested their retromer-binding compound (R55) in cultured neurons, retromer levels increased and AÎ² decreased. The next step is to test the clinical effects of R55 in mice.
Dr Ringe is one of the authors of this study. She feels that R55 could present a therapeutic approach that would have fewer adverse effects, since “We’re not trying to change the level to something it is not usually . . . we’re restoring a normal physiological state . . . bringing the cell back to the way it should be.” Although this work is in the early stages, targeting retromer represents another approach to be added to the armamentarium of AD treatments.
In 2011, President Obama signed the National Alzheimer’s Project Act (NAPA) that strives for effective treatments by 2025.23 This act, along with current AD research efforts, indicates that although the fight continues, strategies for combating AD may be within sight.
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