I have a container of powdered HMB. Unfortunately, I should have bought the capsules. It ruins the flavor of everything I put it in, so I have not really taken very much of it.
2 Likes
medaura
#103
Yeah Iād been warned so I got capsules but only take them once in a while. Need to put them in pill organizers so I actually take them.
1 Like
adssx
#104
Random Chinese university and journal but bad news: Mendelian randomization analysis of lipids traits and lipid-lowering drug-targets in relation to cognitive status 2025
Mendelian randomization reveals no causal link between lipid traits and cognition;
NPC1L1 inhibition genetically linked to higher cognitive impairment risk;
Ezetimibeās cognitive effects may be independent of lipid-lowering action;
Findings highlight caution when prescribing ezetimibe to cognitively impaired patients.
A_User
#105
That looks like p-hacking to me if they used 9 drug targets + lipids, and on top of that multiple different outcomes and six different datasets (and found a genetic correlation in three):
2 Likes
I wonder how much care we need to put into interpreting Mendelian randomization studies due to linkage disequilibrium types of effects. The rarer is any given mutation that drives the result, the more likely it would tend to be packaged with some other mutations that impact things we care about. If mutation A that causes lower LDL-C comes along with mutation B that causes X, should we conclude that lowering LDL-C also lowers X? We should not unless there is a sensible mechanistic story and observational evidence showing some relationship between LDL-C and X independent of the MR study.
2 Likes
adssx
#107
Itās possible. Might explain why itās published by the āDepartment of Anesthesiologyā (lol) of a university in the random āJournal of Affective Disordersā. If it was of higher quality it would be published in Brain by a Stanford team. Iām sure other teams looked at ezetimibe MR and dementia and found nothing and didnāt publish anything.
3 Likes
Null results are still valuable results. They should be published. If they have them, but didnāt publish, thatās a pity. I am not aware of it either way.
3 Likes
adssx
#109
Actually I was wrong, some good researchers published this null result in a good journal: Lipid lowering and Alzheimer disease risk: A mendelian randomization study 2019
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 = 1.23ā1.69). 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.
3 Likes
Thatās 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 donāt always align.
Concerning about PCSK9i and AD though.
2 Likes
Beth
#111
Huge sigh 
I have one apoe4 and I take repatha
Oh well, I guess my chances of an MI are greater than AD, soā¦.
1 Like
On first pass, I was disappointed that the genetic deficiency of NPC1L1 does not protect against Alzheimerās 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 Alzheimerās risk. My earlier hope was based on prior research that showed ezetimibe lowers the risk of Alzheimerās 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 Alzheimerās 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.
