What’s New in the War on Alzheimer Disease?
What’s New in the War on Alzheimer Disease?
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: β-amyloid (Aβ) protein was identified in 1984 in brain plaques of patients with AD, and hyperphosphorylated τ 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 Aβ 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 β-secretase-1 (BACE1) and γ-secretase were proposed as enzymes that prune APP, with the deadly effect of creating Aβ 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 β-amyloid vaccine. Mouse AD models offered initial promise, since vaccinated transgenic animals showed improved learning and memory, and brain Aβ 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–β-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.”