New Information Emerges On Alzheimer’s Risk Factor ApoE4

The ApoE4 variant of the ApoE gene can hugely increase risk of Alzheimer’s disease, but how? A new study has discovered it interacts with 1700 genes

Inheriting copies of the harmful allele ApoE4 seriously raises your risk of developing Alzheimer’s disease, even more so when two copies are passed down. There are 3 known alleles of ApoE: the harmful ApoE4, ‘normal’ ApoE3 and the potentially beneficial ApoE2 which is very rare. ApoE3 is by far the most common of the bunch, and around 80% of the world’s population carries at least one copy of this variant. Around 75 million Americans carry one copy of ApoE4, and around 7 million carry two, making them far more vulnerable to the condition.

Credit: alzdiscovery.org/

Unravelling ApoE4’s harmful effects

Research at UCLA and The Buck Institute has uncovered that ApoE4 acts like a transcription factor, entering the nucleus and strongly binding to DNA. It binds to the key promoter region for around 1700 genes, meaning it has an extremely broad effect on gene transcription. 

“When the genes whose promoters bind ApoE4 are considered in functional groups, their relationship to Alzheimer’s disease is striking. ApoE4 targets genes associated with sirtuins and aging, insulin resistance, inflammation and oxidative damage, accumulation of amyloid plaques and tangled tau among others. This provides a roadmap for what is essentially a ‘unified theory’ of Alzheimer’s disease”

ApoE4 targets aging related genes

SIRT1’s, Sirtuin1, dimer structure

The most striking finding of the research was that a lipoprotein, chiefly involved with fat transport around the body, could be such a wide-ranging transcription factor. The fact it was interacting with genes like SIRT1, a key ‘anti-aging’ target, and reducing the expression of this gene in the brain is potentially an extremely valuable insight. Understanding exactly how this allele can so sharply raise Alzheimer’s risk could pave the way for new therapeutics. 

“Our group hopes this work will lead to a new type of screen for Alzheimer’s prevention and treatment.We are also designing and engineering novel drug candidates that target not one, but several of the ApoE4 mediated pathways simultaneously. Ultimately we want to develop a drug that can be given to ApoE4 carriers that would prevent the development of Alzheimer’s disease, and these results provide a mechanism and screen to do that”

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