New research on the role of a notorious Alzheimer's gene variant could pave the way to treatments that slow down or halt the disease.
Scientists found that the mutant gene, ApoE4, is directly linked to brain damage caused by knots of protein within neurons called tau tangles.
They believe targeting the gene could theoretically prevent the neurological destruction caused by Alzheimer's, for which there is currently no cure.
Lead researcher Professor David Holtzman, from Washington University School of Medicine in the US, said: "Once tau accumulates, the brain degenerates.
"What we found was that when ApoE is there, it amplifies the toxic function of tau, which means that if we can reduce ApoE levels we may be able to stop the disease process."
ApoE4 was identified as a major risk factor for Alzheimer's disease 25 years ago.
It increases a person's risk of developing the condition by as much as 12 times.
But precisely why the gene variant is so hazardous has not been clear until now.
The scientists set out to investigate the role of ApoE, which comes in a range of different forms, or variants, in mice whose brains contained potentially toxic human tau protein.
They compared mice that lacked any version of the ApoE gene or were engineered to have one of three human variants, ApoE2, ApoE3 or ApoE4.
By the time they were nine months old, mice carrying the human variants had suffered widespread brain damage.
The hippocampus and entorhinal cortex regions, important for memory, were shrunken and fluid-filled spaces in the brain expanded as neurons died off.
Mice having no ApoE displayed virtually no brain damage, despite possessing the dangerous tau.
In addition immune cells in mice with ApoE4 triggered a fierce inflammation response not seen in the other animals.
"ApoE4 seems to be causing more damage than the other variants because it is instigating a much higher inflammatory response, and it is likely the inflammation that is causing injury," said Prof Holtzman.
Although the ApoE2 variant is thought to be protective, even this had some degree of harmful effect in the presence of toxic tau, he said.
A follow-up study of brain tissue samples from 79 people who had died from tau-related conditions other than Alzheimer's showed greater levels of damage in those who had ApoE4.
The new findings appear in the journal Nature.
ApoE is involved in the transport of cholesterol around the body via the bloodstream.
Rare individuals who lack the gene altogether suffer from very high cholesterol levels and if left untreated, die young from heart disease.
However, missing ApoE does not appear to affect their brains.
"There are people walking around who have no ApoE and they're fine cognitively," said Prof Holtzman.
"It doesn't appear to be required for normal brain function."
The research suggests that suppressing ApoE activity in the brain could slow down or block neurodegeneration, even in people who have already accumulated tau tangles.
Most experimental Alzheimer's treatments have focused on another brain symptom of the disease, clumps of beta-amyloid protein.
None of these has proved successful, the scientists pointed out.
Prof Holtzman said: "Assuming that our findings are replicated by others, I think that reducing ApoE in the brain in people who are in the earliest stages of disease could prevent further neurodegeneration."
Copyright (c) Press Association Ltd. 2017, All Rights Reserved. Picture - Photo issued by Washington University of the brain of a mouse carrying the Alzheimer's gene variant ApoE4 (left), compared to the brain of a mouse without the gene variant. (c) Yang Shi / PA Wire.