Disappointingly, and somewhat surprisingly, two drugs aimed at halting alzheimer’s disease by reducing levels of the amyloid protein in the brain have failed in a late-stage clinical trial. The clinical trial sponsored by Washington University, called DIAN-TU, employed two drugs, both of which are antibodies, to lower brain levels of amyloid. Amyloid has long been implicated in the disease, and by definition, is always present in the brain of Alzheimer’s patients. However, the exact role of amyloid in triggering the disease has come under question as numerous drugs aimed at lowering amyloid levels in the brain have failed in late stage– and very expensive– clinical trials.

The DIAN-TU study was uniquely geared toward achieving a positive result with amyloid lowering drugs, as all participants had rare genetic errors that raised the probability of developing early-onset Alzheimer’s to nearly 100%. The age of onset of these rare forms of Alzheimer’s disease is in the forties or fifties, and the age of onset in these genetic carriers tends to be extremely constant within any particular family. Because of this onset predictability, it is possible to design studies where members of such families receive treatment prior to the development of any clinical signs or symptoms. These studies are called primary prevention trials, and in the DIAN-TU study, most subjects showed no signs or symptoms when treatment began. The two antibody-drugs used were called Solanezumab, made by Eli-Lilly, and Gantenerumab, made by Roche. Both of these make their way into the brain and bind amyloid, eventually reducing its levels in the brain. In the case of Solanezumab, patients received the drug for four years on average, and in the case of Gantenerumab, for five years on average, with some subjects taking the drug for as long as seven years. Despite these long treatment durations, neither drug showed any benefit on the reduction of cognitive decline over placebo. This is the only current information available for this study, but important detail will be disclosed at an up-coming Alzheimer’s Disease conference in April.

Scientists from the Roskamp Institute will eagerly await those details because critical questions are outstanding. For instance, were the drugs actually able to reduce amyloid levels in the brain? This is extremely important because if the drugs were indeed able to lower amyloid levels, but there was no benefit to the patient, then we must consider that the particular forms of amyloid that these drugs target are not important for the development and progression of cognitive decline. However, if the drugs do not show reduction in amyloid levels, then the trial will have failed because the drugs did not do the job they were designed to do in these subjects. These and many other questions will be at the forefront of the minds of scientists around the world who will gather to hear details of these results as we try to understand exactly why drugs targeting, what seems to be the center of this disease in these early onset cases, have failed. In the long struggle against Alzheimer’s disease, scientists and clinicians alike have continued to learn from these setbacks and, thankfully, patients and their caregivers continue to take part in these important studies as we learn the most appropriate way to slow, and eventually stop, this disorder.

Although scientists at the Roskamp Institute were among the first in the world to discover that genetic mutation of the amyloid gene was inextricably linked to early-onset familial disease, they, and their colleagues are continuing to look for ways to stop the disorder including, but certainly not limited to, reduction of amyloid levels. For instance, we are pursuing other genetic clues to the cause of Alzheimer’s disease and are also targeting Tau, another critical protein in the development of disease. In addition to these molecules, we also know that inflammation plays a critical role in initiating and perpetuating the disease, and as well as developing new drug treatments at the institute, we are helping our patients by relaying what we have learned about environmental factors and lifestyle choices that can influence the disease’s onset and progression.

Together, the combination of indomitable persistence by scientists and the gracious willingness of patients and their caregivers to take part in such studies will inevitably result in the demise of this devastating disorder.

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