Can we reverse Alzheimer's?

New approaches from Harvard offer hope.

Finding a way to prevent Alzheimer's disease (AD), or to reverse the damage it does, is one of medicine's great challenges as we enter 2013. Over the past 20 years, great progress has been made in understanding the changes in brain chemistry that lead to AD. Yet translating this knowledge into treatments has been difficult. Witness the collapse of two major AD drug trials this past autumn (solanezumab and bapineuzumab). But two Harvard doctors are forging ahead with entirely new approaches that offer hope for meaningful treatment in the near future.

About the disease

Alzheimer's is one of the most common forms of dementia. The death of brain cells in AD has been linked to two proteins called beta-amyloid and tau. Beta-amyloid forms the plaques and tau forms the tangles seen under the microscope in the brains of patients with AD. The plaques and tangles distinguish AD from other types of dementia. AD symptoms include debilitating confusion, memory loss, irritability, and anxiety. The disease is eventually fatal.

PBT2

The first new approach to fight AD comes from Dr. Rudy Tanzi, the Joseph P. and Rose F. Kennedy professor of neurology at Harvard Medical School. He was among the scientists who discovered the first AD genes back in the 1980s. Now he's helping to map the rest of the genes linked to AD.

Tanzi also helped create PBT2, a drug that's now in phase 2 clinical trials in Australia. Unlike the recently failed drugs, which use antibodies to attack beta-amyloid, PBT2 takes another approach. Certain metals in the brain (copper and zinc) help drive production of the plaques and tangles. PBT2 prevents this from happening. "It takes the metal away from the amyloid protein so it can't form plaques. It removes metal that was trapped and makes it available again for dozens of brain functions like gene activity and antioxidant health. PBT2 also keeps tangles from forming. And finally, it induces new neurons to grow in the hippocampus, which should improve executive function," says Dr. Tanzi.

Results from the initial animal trial and the first two clinical trials were encouraging, with no significant side effects. "They've only been small trials, with less than 100 people, but we've seen significant improvement in executive function in just 12 weeks," he says. "It remains to be seen how it works on overall memory."

Scientists are now testing PBT2 in combination with imaging techniques to get a visual picture of how effective the drug is in removing amyloid plaques. If all goes well, the drug will progress to larger clinical trials. If PBT2 proves effective in larger studies, Dr. Tanzi is hopeful it may be available to people with AD in about five years.

Neuro AD

The second new approach is Neuro AD, a treatment developed in Israel for the management of AD symptoms. Neuro AD challenges a person to solve problems on a computer right after it uses noninvasive electromagnetic energy to stimulate the brain region required to give the answer. Typical problems include matching shapes, remembering words, and completing a sentence. Treatment lasts about an hour a day, every day for six weeks. And the results? "It doesn't cure the disease, but it does make the brain circuits work better, and this leads to a striking improvement in cognitive abilities for day-to-day tasks," says lead researcher Dr. Alvaro Pascual-Leone, professor of neurology at Harvard Medical School. "Patients are able to recall names of people they see, remember what people tell them, find their way in the supermarket, and recall things to buy."

So far, two small controlled trials have been completed, and a larger trial is under way at Harvard as well as sites across the country. The only side effects so far have been mild headaches. And while the treatment (cost, about $5,000) is already approved in Israel and some countries in Europe, Dr. Pascual-Leone emphasizes the need for more studies. "We've only done small trials, and we don't know how long the effects last beyond three months. I understand the desire to get access to cutting-edge treatments, but it's important to gather sound scientific evidence."

Yet he is cautiously optimistic, especially about combining Neuro AD with other approaches, such as medication. "Ultimately," says Dr. Pascual-Leone, "the treatment for Alzheimer's may not be one thing or another, but a combination of things."