For two decades the dominant theory among Alzheimer’s researchers has been that the disease begins with the deposition of beta-amyloid plaques in the brain, which trigger a cascade of other damaging events—including the appearance of the other classic marker of the disease, neurofibrillary tangles. Now some researchers propose looking further back in the disease process for molecular mechanisms that can separately trigger the pathways for both the plaques and the tangles.
Lending credence to this “dual pathway hypothesis” is the fact that every anti-amyloid drug tested so far has failed to slow the progress of Alzheimer’s in large-scale clinical trials. Meanwhile, therapies targeting the tangles—which are made of an abnormal form of a structural protein known as tau—have shown promise in small trials, even though the “tau pathway” becomes active relatively late in the disease.
“Either amyloid-beta sets off the tau pathway and the tau pathway cannot be stopped” by clearing amyloid, “or there is a driver upstream that sets off both the amyloid and tau pathways,” says Karen Duff, an Alzheimer’s researcher and noted mouse-model developer at Columbia University Medical Center.
With neurologist Scott Small, also at Columbia, Duff recently proposed that researchers look more closely at the dual-pathway possibility. If verified, it would shake up the Alzheimer’s research field and provide a host of new targets for potential drug therapies.
In the past few years Duff and other researchers have found several factors that could drive the disease via both the amyloid-plaque and tau-tangle pathways. One is a cholesterol-transport protein known as apolipoprotein-E, whose E4 variant (Apo-E4) was linked by Duke University researchers in 1991 to a higher risk of developing the common, late-onset form of Alzheimer’s. Apo-E4 is the only known major genetic risk factor for late-onset Alzheimer’s. The 1 to 2 percent of people who have two copies of Apo-E4 have more than 10 times the usual Alzheimer’s risk, tend to be diagnosed much earlier and, in some postmortem studies, have shown higher levels of both amyloid plaques and neurofibrillary tangles.
Researchers generally agree on the link between Apo-E and beta-amyloid. Secreted from microglial cells, Apo-E proteins bind to beta-amyloid and appear to play a role in clearing it out of the brain. The evidence suggests that the E4 variant is less efficient at this clearance, allowing more beta-amyloid to accumulate.
Apo-E could also drive the tau pathway. “The more likely way that Apo-E could have an effect on tau, independent of anything to do with amyloid-beta, would be through Wnt signaling,” Duff says.
The Wnt signaling pathway is one of the brain’s most basic molecular signaling pathways. Apo-E interacts with this pathway via cholesterol-related receptors on brain cells. Apo-E4 hits these receptors in a way that inhibits Wnt signaling and thereby increases the production of an enzyme known as GSK3, a “kinase” that helps proteins such as tau attract phosphate molecules. This phosphorylation process in turn makes tau more likely to separate from neuronal structures and form into tangles.
Duff calls this idea of a connection between the Wnt pathway and tau tangles “quite compelling,” not only because it is reasonable biologically but also because some preliminary evidence links Alzheimer’s risk to genetic mutations that affect cholesterol-related brain-cell receptors. Moreover, the link between GSK3 and increased tau phosphorylation is already strong. Evidence also indicates that increased GSK3 activity separately affects the processing of beta-amyloid, potentially raising its levels in the brain.
More work, especially in animal models, may establish that a dual-pathway mechanism applies to the common, late-onset forms of Alzheimer’s. “It’s not quite there,” Duff says. Sam Gandy, a researcher at Mount Sinai School of Medicine who in the 1980s also investigated the possibility that Alzheimer’s was a dual-pathway disease, suggests that researchers “study the brains of an aging population [as they develop Alzheimer’s] and look for the earliest pathological event, prior to any amyloid disturbances.”
Role of aging
Gandy also emphasizes that a dual-pathway hypothesis will never explain all forms of the disease. Some rare genetic forms of Alzheimer’s are caused by mutant genes that increase the level of beta-amyloid; a single, amyloid-related mutation in these cases ultimately leads to all other characteristics of the disease, including neurofibrillary tangles. Such cases had helped to persuade many researchers that a single pathway, starting with beta-amyloid, was all that is needed to explain the disease.
Duff is working for now with mouse models of Alzheimer’s to establish better evidence that dual pathways are active. She also thinks that the search for upstream triggers of disease is likely to lead eventually into the gray area of the aging process itself.
“Alzheimer’s obviously is related to normal aging, and there are a number of things that start to go wrong in the brain [with aging] that could set off relevant pathologies, such as aberrant kinase activities and especially aberrant clearance mechanisms.”
In any case, she says, the response from other researchers to her suggestion that dual pathways may be at work in Alzheimer’s has so far been positive. “It seems that opening this up for discussion and looking beyond the anti-amyloid-beta therapies is widely viewed as a good thing.”