ApoE4, a-beta, and Alzheimer's disease susceptibility

Professor Dennis Selkoe discusses the degree to which the ApoE4 gene is associated with early onset Alzheimer's disease.

One of the most important risk factors for Alzheimer’s [disease] is this gene called ApoE4. If one has one or even two copies – two copies means one from Mom and one from Dad – you are predisposed to having a higher likelihood of Alzheimer’s [disease]. But, importantly, that tendency to Alzheimer’s [disease] won’t really show itself until you are in your sixties or your fifties, and it is true that a-beta levels may build up in the brain far earlier than that, maybe in the twenties or thirties or forties. But there is little evidence that it builds up already at five or seven, or ten, or two years old, etc. So, while it is true that ApoE4 carriers will eventually build up too much a-beta, and they’ll do it much earlier than the typical Alzheimer’s [disease] patient, who won’t start building it up until 50 or 60, they’ll do it earlier than that. But I don’t have evidence from anything I know that they’ll build up a-beta per se already at two or five or ten. They may build it up, but it may be later than that. What I do know, though, is that ApoE4 is a complex and tricky protein. It can cause changes in cortical thickness and cortical health independent of its acceleration of a-beta buildup, so I am aware of studies in ApoE4 carriers, even by functional MRI or MRI imaging, that ApoE4 inheritance in a person will change cortical thickness and that kind of thing. But I am not aware that, if cortical thickness is altered in early life, that can be attributed to the a-beta problem coming from ApoE4. That has been a bit of a debate in the field. It’s clear that ApoE4, compared to the other two ApoEs (E3 and E2) will cause the brain to develop somewhat differently and cause the thickness of the cortex or certain neuronal connections to be different, and science hasn’t figured out yet whether that’s a separate, effective ApoE4 [rather] than it’s acceleration of a-beta buildup. In my view, I don’t think we have enough information to say that everything that goes wrong in the nervous system with people who have ApoE4 can be attributed to a-beta, to that part of the problem. I think it may be true, true, and unrelated.