Nearly a quarter century ago, a genetic variant known as ApoE4 was identified as a major risk factor for Alzheimer’s disease — one that increases a person’s chances of developing the neurodegenerative disease by up to 12 times. However, it was never clear why the ApoE4 variant was so hazardous.

Now, a study shows that the presence of ApoE4 exacerbates the brain damage caused by toxic tangles of a different Alzheimer’s-associated protein: tau. In the absence of ApoE, tau tangles did very little harm to brain cells.

The findings suggest that targeting ApoE could help prevent or treat the brain damage present in Alzheimer’s disease, for which there are currently no effective therapies.

Alzheimer’s, which affects one in 10 people over age 65, is the most common example of a family of diseases called tauopathies. To find out what effect ApoE variants have on tauopathies, the researchers turned to genetically modified mice that carry a mutant form of human tau prone to forming toxic tangles.

The researchers studied mice that lacked their own version of the mouse ApoE gene or mice with replacements of the three variants of the human ApoE gene: ApoE2, ApoE3 or ApoE4.

By the time the mice were 9 months old, those carrying human ApoE variants had widespread brain damage. ApoE4 mice exhibited the most severe neurodegeneration, and ApoE2 the least. The mice that lacked ApoE entirely showed virtually no brain damage.

Further, the immune cells in the brains of mice with ApoE4 turned on a set of genes related to activation and inflammation much more strongly than those from ApoE3 mice. Immune cells from mice lacking ApoE were barely activated.

Next, the researchers set out to determine whether ApoE in people similarly exacerbates neuronal damage triggered by tau. After studying autopsy samples from 79 people who died from tauopathies, they found that people with ApoE4 had more damage than those that lacked ApoE4.

These findings suggest that decreasing ApoE specifically in the brain could slow or block neurodegeneration, even in people who already have accumulated tau tangles. Most investigational therapies for Alzheimer’s disease have focused on amyloid beta or tau, and none has been successful yet in changing the trajectory of the disease. Targeting ApoE has not yet been tried.

Researchers are hopeful that if their findings are replicated, reducing ApoE in the brain in the early stages of neurodegenerative disease could prevent further neurodegeneration.

Paper: “ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy”
Reprinted from materials provided by Washington University School of Medicine.

January 17, 2018