Wouldn't low plasma ApoE reflect low synthesis by the liver? And regarding high apoE in CSF, are you suggesting that is not from astrocytes, but rather peripheral apoE crossing the BBB?alangreenmd wrote:High APOE in CSF associated with AD reflects leaky BBB.
Low APOE in plasma probably reflects low synthesis by astroctes.
Problem with APOE4 is lack function. Therefore if in old age E3 synthesize less will cause less function. In mouse studies APOE null mice same as APOE4 mice.
Decrease APO3 in old age good explanation some risk AD in non-E4 in old age.
ApoE4 loss of function vs. toxic gain of function, at least as far as brain function, has been a debate for 20 years. The recent work by David Holtzman's Lab in mice expressing human apoE crossed with a Tau mutant causing frontal-temporal dementia suggests that ApoE4 may be a toxic gain of function https://www.nature.com/articles/nature24016.
Whether one would want to decrease apoE or increase apoE remains a matter of debate, although the data suggesting low apoE expression is more correlated with disease does suggest lowering might not be the end-all-be-all approach.