A new study is changing how scientists think about Alzheimer’s disease

How does ApoE4 do its dirty work? Since 1993, when this variant of the apolipoprotein E gene was found to multiply the risk of the most common form of Alzheimer's disease as much as fourfold, researchers have probed its connections to β-amyloid, the dominant suspect for the cause of the illness. This protein fragment forms extracellular "plaques" that can disrupt brain signals and kill neurons. This week, however, one of the main proponents of the hypothesis that ApoE4 exacerbates amyloid pathology stunned many of his colleagues by showing that its most toxic effects may result from a damaging immune response to a different protein: tau.

"This is a seminal study" and has "profound clinical implications," says Bob Vassar, a molecular biologist at Northwestern University in Chicago, Illinois. The study also shifts the terms of an old debate over whether Alzheimer's treatments should focus on tau or amyloid, by suggesting both could be targeted through ApoE4. Because David Holtzman, the leader of the new study, has long championed a link between ApoE4 and β-amyloid, "it's very compelling to hear him argue now" that tau is central to ApoE4's dangerous influence, says Scott Small, a neuroscientist at Columbia University.

People with Alzheimer's disease die with brains riddled by both amyloid plaques and intracellular tau "tangles." Yet the evidence linking tau to ApoE4 has been indirect and circumstantial, says Holtzman, a neuroscientist at the Washington University School of Medicine in St. Louis in Missouri. In any case, scientists doubted that tau—normally a stabilizing protein within cells—could escape from neurons to interact with the cholesterol-ferrying protein made by ApoE, he says.

That turned out to be wrong. "When we learned that some tau actually escapes cells and that pathological forms can spread from to cell to cell, we thought maybe it is tenable to retest this."

For the new study, published today in Nature , Holtzman and colleagues took genetically engineered mice that produce a version of tau found in the brains of people with a neurodegenerative disease similar to Alzheimer's, and cross-bred them with strains expressing ApoE4 or the two other main human variants of ApoE: E2 and E3. They also crossed the tau mice with mice in which its ApoE had been disabled. When the team examined brain tissue in the four resulting strains, all the mice carrying the human variants of ApoE had tau tangles and neurodegeneration, with the most profound tissue loss in E4 mice. In the taumaking mice with no ApoE gene, however, there was little or no neuronal death.

That result alone "provides definitive evidence" that ApoE plays a major role in tau pathology, says Gary Landreth, a neuroscientist at Indiana University in Indianapolis.

Equally compelling, he and others say, was what happened when Holtzman's team took microglia and astrocytes—the brain's immune cells—from mice that express human ApoE4 and grew them in culture with neurons that contain the human tau. The immune cells launched an inflammatory response that appeared to kill neurons en masse. "This is a brand-new mechanism by which ApoE influences both Alzheimer's and other tauopathies, by affecting the innate immune response," Holtzman says.

Holtzman and others now believe that β-amyloid plays an important role in triggering the onset of Alzheimer's disease, with tau deposits creating later damage. "Gone are the days when we had these competing camps" of tau versus amyloid, says Dennis Selkoe, a neurologist at Harvard Medical School in Boston and an architect of the amyloid hypothesis. "It's both—a double whammy." But, he adds, the study reveals an important new target for treatments: the destructive conspiracy of pathogenic tau and ApoE4.