Why Does ApoE4 Increase Alzheimer's Risk?

Credit: Salk Institute

Carrying 1 or 2 copies of a particular gene ApoE4 increases risk of developing Alzheimer's disease as well as lowering the age of onset, but how does it do it?

There are 3 different alleles for the ApoE gene: ApoE2, ApoE3 and ApoE4. The E2 variant of the gene is the rarest, but luckily for some is protective against Alzheimer's. E2 is the most common of the bunch and  is relatively 'neutral', whereas E4 comes with a significantly increased likelihood of developing Alzheimer's. Regardless of which version of the gene you have however, all are involved in transporting vitamins, cholesterol and fats through the body. 

We still don't know what actually causes Alzheimer's disease, but there are two associated processes: tau and beta amyloid. It's been thought for some time that ApoE4 may impair the ability to properly process or clear out harmful beta amyloid molecules, but it wasn't known why. Previous research has shown that ApoE4 may degrade differently to the other variants, and so a team of researchers decided to analyse how a particular enzyme called high-temperature requirement serine peptidase A1 (HtrA1) degraded ApoE4. 

"There's been an idea tossed around that ApoE4 breakdown products could be toxic. Now, knowing the enzyme that breaks it down, we have a way to actually test this idea"

When the scientists compared how the enzyme HtrA1 degraded both ApoE3 and ApoE4 they found ApoE4 was processed far more - resulting in smaller, unstable protein fragments. This means that individuals with ApoE4 could potentially have less ApoE protein actually available in their brain, as it was being broken down far more in comparison. 

Curiously, the team also found that becuse ApoE4 bound HtrA1 so effectively, it inhibited tau breakdown by the same enzyme. Tau tangle formation is strongly associated with neuronal death, so this could go some way in explaining why risk is increased so notably. 

"People have thought about tau or amyloid beta as things that cause Alzheimer's, but this suggests that we need to think more globally about proteins that could be impacting tau or amyloid through biochemical pathways" 

Read more at MedicalXpress