ApoE variants are the strongest known genetic risk factor not just for Alzheimer's disease (AD), but for any disease. It was first described just about 25 years ago. "And I've worked on it since then," David Holtzman told BioWorld.

In those 25 years, it has become clear that individuals with at least one copy of the ApoE4 variant, rather than ApoE3 or the protective ApoE2, have drawn the short stick in pretty much every aspect of the disease. They are more likely to develop AD in the first place, they do so at a younger age, and the disease progresses more quickly.

Less progress has been made, though, on how ApoE4 does its damage. "It's very clear that ApoE interacts with amyloid," Holtzman said. Still, "nothing's ever been completely solidified with respect to its role in neurodegeneration."

Partly, that's due to the fact that much of the research into ApoE has focused on its interaction with amyloid-beta – with good reason, since amyloid beta and ApoE are both secreted proteins that mostly reside in the extracellular space, and ApoE binds to amyloid beta and is present in amyloid plaques.

Still, despite all of the work that has gone into it, amyloid-beta's role in AD is still poorly understood. Indeed, one of the bigger mysteries of the field is the disconnect between the scientific evidence, which clearly implicates amyloid beta in AD, and the trash heap of amyloid-targeting agents that have failed in clinical trials.

In the Sept. 20, 2017, issue of Nature, Holtzman, who is professor and head of the Department of Neurology at Washington University in St. Louis, and his colleagues reported that ApoE4 also interacted with AD's second culprit, tau, and that this interaction was "an additional important mechanism for how ApoE contributes to brain damage in AD," he said.

While amyloid is "important in instigating the disease, but . . . not sufficient" for developing clinical-stage AD, Tau protein tangles are "directly correlated and almost certainly causal" in the neurodegeneration that underlies AD.

Furthermore, Holtzman said, "in the last 10 years or so, there's a lot of evidence that the pathological forms of tau that accumulate . . . spread around the brain as the disease progresses, in a prion-like fashion," which means that "there is almost certainly an extracellular phase of tau" that can interact with ApoE.

In studies with genetically engineered mice that expressed a dementia-causing form of human tau, Holtzman and his team showed that the animals only developed neurodegeneration when ApoE was present. The ApoE4 allele did more damage than ApoE3 and ApoE2, but any form of ApoE was harmful. Knockout mice lacking ApoE in the brain had very little damage from the mutant tau.

Tau tangles are a feature of not just AD, but a group of diseases collectively known as the tauopathies. The team also looked at postmortem brain samples from individuals who suffered from tauopathies other than AD, and showed that here, too, those with the e4 version of ApoE had worse neuronal damage.

Holtzman and his colleagues plan to look at both the molecular details of the interaction between ApoE and tau, and the cell types where the interaction plays a role.

"The main findings from this work suggest that ApoE modulates the inflammatory response, and in doing so, modifies damage," Holtzman said. But the steps along that path, and whether they are primarily happening in neurons, glial cells, or immune system cells, remain to be worked out.

The team also wants to "determine whether lowering ApoE is really a target" for clinical intervention in the tauopathies, he added.

The data his team published are in line with some earlier studies in suggesting that "if you lower ApoE levels in the brain, that is going to be protective."

Genetic studies suggest that such brain-specific lowering of ApoE is in principle a viable therapeutic approach. While ApoE is critical for cardiovascular functioning, there are individuals who naturally lack ApoE altogether, and their problems are cardiovascular, not cognitive.

However, he cautioned, in the experiments now described in Nature, "ApoE is either present or absent from before the animals are born."

Whether lowering ApoE can still be protective by the time an individual has clinical symptoms of AD or another tauopathy is very much an open question – as those in the AD field will appreciate. One of the major theories with respect to why targeting amyloid beta has been such a clinical failure is that such interventions come too late.

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