The pressure to find treatments and preventions for Alzheimer's disease and other dementia-related diseases has been building steadily over the past decade, and it is becoming critical as the United States prepares for an increasing number of people who are approaching the age of 65, an age where the likelihood of the onset of dementia-related diseases increases. Aside from the personal losses to individuals and families, the needs of those patients will be an enormous burden on the nation's health care system, doctors say. In California alone, almost half a million people are living with Alzheimer's now, and that number is expected to climb to 660,000 by 2025, according to the Alzheimer's Association.
One solution has been to focus on one aspect of the change in brain physiology, the amyloid beta. This focus has been a twofold problem. First, amyloid beta is most likely one piece of a long chain of events that go wrong in the brains of people with Alzheimer's. And second, the plaque buildup likely has been going on for years, even decades, before people are symptomatic. In the past 10 years, amyloid therapies have failed, one after another, to provide significant benefit to people even with mild dementia. That is not to say that scientists are giving up on amyloid beta, and it's still a primary focus of Alzheimer's research in the United States. The scientific community and the major drug developers have devoted decades of resources into studying amyloid beta. There is little doubt that the protein is important, and it may indeed be a viable target for drugs to treat the disease someday. But in the meantime, scientists are looking for other targets, and they are trying to dig much deeper into the history of the disease and identify the earliest signs of it in people who are not symptomatic yet.
At Stanford, scientists have focused on the communication lines, called synapses, which allow neurons in the brain to talk to one another. Synapses are created to help build memories and learn new skills, but synapses also must be pruned to keep brain activity healthy and efficient. Scientists are coming to believe that in brains afflicted by Alzheimer's disease, that pruning process becomes overactive. Synapses that help people retain memories and create new ones are snipped and cannot be repaired. Eventually, the neurons on either end of the synaptic connections die. A current idea is that the sickness starts earlier than previously thought.
To study the earliest phases of a disease, scientists seek to be able to identify future patients long before they complain of symptoms, like memory loss. That is why the most attractive targets for early Alzheimer's interventions may be found in people who are known to have a genetic risk for the disease. There has been growing interest in the gene called ApoE (Apolipoprotein E), in particular. There are three versions (isoforms) of the gene, and one of them—called ApoE epsilon 4 (e4)—is associated with an increased risk of developing Alzheimer's. People with one copy of the ApoE e4 allele are three times more likely to get Alzheimer's than someone with a healthy variant; two copies of the e4 allele increase the risk 10- to 12-fold. Scientists at San Francisco's Gladstone Institute of Neurological Disease have identified a potential drug that alters the ApoE e4 isoform to make it behave more like its healthy siblings. The drug is in the earliest stages of laboratory and mouse study and is not yet ready to test in humans.
The focus of development efforts have also been directed to monotherapies. These efforts have been deficient in providing a significant improvement in treating Alzheimer's.
To date, no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment.