Journal of the American Association (February 15, 2017): Alzheimer Outlook Far From Bleak

Publication Date: 
Sat, 02/18/2017

Last summer, deep disappointment befell the Alzheimer disease (AD) community when study results showed that the widely heralded experimental drug LMTX had failed to help AD patients. In November, another promising drug, solanezumab, also dashed hopes. Because these drugs target either amyloid β (solanezumab) or tau (LMTX), proteins that aggregate into the plaques and tangles in brain tissue characteristic of AD, some have suggested that researchers are following the wrong path by attacking these proteins and that AD research is back to square one after decades of work.

Recently, JAMA sat down with 2 prominent authorities on AD, Rudolph Tanzi, PhD, of Harvard University, and Berislav Zlokovic, MD, PhD, of the University of Southern California (USC). Tanzi has been exploring the genetics and progression of AD for more than 30 years, while Zlokovic’s work has emphasized the cerebrovascular system’s important role in the etiology. They discussed what the future holds for AD research and whether the picture is as gloomy as some believe. The following is an edited version of that conversation.

JAMA: Dr Tanzi, what was your take on these recent drug failures? Have you become pessimistic?

DR TANZI: Actually I'm quite optimistic. Most of us in the field are not surprised LMTX failed. I frankly don't think it was that strong of a drug going in. All the first genes we found [eg, amyloid precursor protein (APP) gene and presenilin genes ] told us amyloid causes this disease, and the debate arose because when we put the genes into mice, they’d make amyloid and eventually have enough inflammation in the brain to get cognitively impaired but they didn't get tangles. They didn't get all 3 pillars of the pathology: plaques, inflammation, and tangles. So the question arose: Is amyloid really causing the disease? I argued, “Well, humans aren’t 150-pound mice.”

Recently, we created what the New York Times called “Alzheimer's in a dish,” a 3D human neuroculture making stem cells that's growing in a gel matrix that mimics the brain. You put in the Alzheimer gene mutations that make amyloid, and afterward you get tangles from endogenous tau protein. You block the amyloid, you block the tangles. That was the first real proof of concept that amyloid can make tangles if you use human neurons in the right environment.