University College London + Cambridge + Karolinska + Utrecht so Tier 1. In Annals of Neurology, Tier 1 as well.
Results:
NPC1L1 (encoding the target for ezetimibe)
Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.
That’s fantastic, and very encouraging. Great harm is done when null findings are suppressed, as it distorts what we know and obstructs hypothesis generation. Unfortunately publishing incentives don’t always align.
On first pass, I was disappointed that the genetic deficiency of NPC1L1 does not protect against Alzheimer’s disease. The NPC1L1 protein in question is central to cholesterol absorption in the bowel and that function is blocked by the drug ezetimibe. So the implication is, in Mendelian Randomization, if that protein is absent due to an allele being disrupted/absent, then that should somehow represent taking ezetimibe in terms of lowering Alzheimer’s risk. My earlier hope was based on prior research that showed ezetimibe lowers the risk of Alzheimer’s and related dementias by > sevenfold. So Mendelian Randomization suggests that is not so, but we are in fact talking about two different mechanisms of action. I really comes down to this: not producing enough NPC1L1 does not increase Alzheimer’s risk, but taking ezetimibe has a different (non-cholesterol) mechanism of action in the brain by presumably lowering the binding of hexokinase-1::14-3-3G protein. That is, ezetimibe has a stronger affinity for that binding site and replacing hexokinase-1 with ezetimibe at that site lowers the risk of AD. My hope in ezetimibe is restored for now.
Just ask your family doc for an rx. I printed out the study and handed it to my family doc. And who does not benefit by lowering cholesterol? It costs $45 for a 90 day supply here in the USA, but cheaper in India when I could get it there.
Very good point - Thanks! Definitely worth it to ask your doctor if he/she will prescribe it for us. I’ll do that now, as I was just thinking of ordering more. Though I do like the combo Ezetimibe/Bempadoic Acid pill that is available from India (that I don’t think we have here in the US).
FWIW, incase you have not seen US sourced ezetimibe, it’s a tiny pill.
I loved the idea of a combo pill, so I bought that from India, too, but then I saw they were fairly large.
My next order from India was only for BA, and I will get EZ from a US pharmacy (the volume of the two pills won’t be larger than the one BZ/EZ pill). My thought was after seeing the poor quality incident with Sun Pharma, I figured there would be slightly less risk in quality with buying US drugs. If the combo pill was actually smaller, then I would throw risk out the window
PS, not all BA is smaller, I specified brand after some great people here showed me their various sizes
Meta-analysis of one-sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C was 0.24 (0.18–0.31) for HMGCR, 0.18 (0.12–0.25) for NPC1L1, 0.97 (0.70–1.35) for PCSK9, 1.66 (0.52–5.36) for ANGPTL4, 1.41 (0.63–3.16) for LPL, and 0.30 (0.26–0.34) for CETP. Cox regression and two-sample Mendelian randomization results were mostly directionally consistent.
Several months ago (before tariffs) I asked my PCP and he gladly prescribed Nexlizet (bempo+ezet) but insurance wouldn’t cover. I read the guidelines for coverage (i.e. failure to adequately respond to statins) and I could have “staged” blood tests to get the numbers they wanted by eating before the blood draw or stopping rosuvastatin and forgetting to mention it during the blood draw, but instead I stocked up on the overseas version, and now have 1200 tabs in a special fridge.
Aah, good on ya! Exactly my approach. Arguing with insurance companies beholden PCPs is entirely pointless. Get the meds yourself. That said, there are limitations to this approach. Not all meds are readily available from places like India, and the current import regimen is under question. I can only hope that the import situation can resolve itself not too long from now.
I grew up before MR studies but it would seem like lifetime exposure is just so different in the world of cholesterol as to make them almost worthless.
Like brain development requires cholesterol so that is a huge problem. Now certainly some cholesterol agents don’t seem to have a negative effect in this study but that may just say they don’t effect cholesterol during brain development.
