Larry Goldstein, famous for his plainspoken attitude, is one of the few big names in the Alzheimer field who bucks the amyloid hypothesis.

Goldstein says the long-favored hypothesis, which proposes that the amyloid-beta protein is the initiating factor in the disease, doesn't adequately explain many observations—such as the poor correlation between the deposition of amyloid plaques and cognitive problems. “It's molecularly not explicit,” he says. “What is it that amyloid does to neurons? Does it activate a receptor, poke a hole, activate kinases? There are a lot of different suggestions, but they're not precise.”

The problem is that humans are not just big mice.

Goldstein, a professor of cellular and molecular medicine and a Howard Hughes investigator at the University of California, San Diego, favors an alternate model that pins the start of the downward spiral in Alzheimer disease to transport defects in the axons of nerve cells. The resulting 'traffic jam' of motor proteins, organelles and vesicles causes the axons to swell, he says, and eventually leads to Alzheimer disease.

In a paper published last year, Goldstein and colleagues identified these defects in postmortem brains from individuals who showed early symptoms of the disease, but no amyloid plaques (Science 307, 1282–1288; 2005). He also identified the defects in mouse models—more than a year before the mice developed classical disease pathology.

Goldstein says one of the big problems in the field is that there are no good animal models of the disease. He is instead turning to human embryonic stem cells that he has coaxed to differentiating into human neurons. “The problem is that humans are not just big mice,” he says. “We don't know that the physiology and biochemistry of the human neuron is identical to that in animals.”