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Research shows potential damaging ApoE4 interaction with tau

For nearly 25 years, Alzheimer’s disease researchers have studied how the ApoE4 gene variant -- known to triple risk for the disease -- interacts with beta-amyloid, a leading culprit for the malfunction and death of neurons that cause cognitive impairment. But recent research has surprised the dementia science community, as it revealed a previously unknown, possibly more damaging interaction between ApoE4 and the protein tau.

The study, published in the journal Nature, may move scientists beyond their debate on whether to focus on amyloid or tau, toward a new way forward that examines both.

A team of researchers led by Dr. David Holtzman of Washington University in St. Louis, cross-bred the P301S transgenic mouse, which mimics human frontotemporal dementia, with a group of transgenic mice that expressed different forms of the ApoE gene. At age nine months, the mice that expressed ApoE4 showed more inflammation, greater deposits of tau, and loss of neurons in the brain than their counterparts. Additionally, non-ApoE4 mice appeared to be insulated from any neurological damage caused by tau.

Neurons expressing human tau showed additional damage when ApoE4 was added.

The next step of the work took immune cells (microglia and astrocytes) from the brains of ApoE4 expressing mice and grew them in a cell culture containing human tau. The tau triggered an inflammatory response that seemed to kill off multitudes of neurons. This gave the team a clear indication of a new mechanism to explore for potential future studies.

This groundbreaking work suggests that, while β-amyloid is a key trigger to the start of AD, it is not the only factor driving the tau accumulations causing additional damage with time. This combination of two dementia risk factors, previously seen as separate, opens vast new pathways for exploration.


Shi Y, et al. ApoE markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017 Sep 28. doi: 10.1038/nature24016. Epub 2017 Sep 20.