It can take years or even decades to properly understand a pathway.  But when a certain threshold is passed, new therapeutic opportunities can be revealed at an exciting rate.  The apolipoprotein E (apoE) pathway has passed that threshold, and VC-backed start ups to exploit this new understanding are springing up like mushrooms.

As early as the mid-1980s, human genetics identified the importance of the apoE protein: a common allelic variant (apoE4) was associated with increased risk of Alzheimer’s Disease, while another variant (apoE2) was associated with longevity.  Even today, the sequence of the apoE gene remains the only really robust association with longevity in humans.

But there is another side to apoE.  As the name indicates, it is a structural component of lipoproteins, and plays a key role in the clearance of triglyceride-rich particles associated with heart disease.  In mice, deletion of the gene encoding apoE leads to a massive hypercholesterolemia and formation of severe vascular lipid lesions resembling human atherosclerosis.  In humans, too, the allelic variants of apoE are associated with abnormal lipoprotein profiles.

How do you make sense of this complicated ‘split personality’ of apoE, with central roles in the seemingly unconnected worlds of neurodegeneration and lipid metabolism?  New research is finally providing the answers, and demonstrates, at last, how to drug this target.  The VC community has been quick to respond, supporting start-ups in this area – can they deliver first-in-class therapies in these blockbuster indications with vast unmet medical needs?

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