#998

Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.

https://www.neurology.org/doi/10.1212/WNL.0000000000207876

#999

That’s an association study. I cited a Mendelian randomization hinting at a causal link between low LDL and dementia.

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#1000

Ok. Here’s a MR paper.

lowering the LDL-C level is expected to be an important choice in retarding or reversing the condition of cognitive decline in AD.

#1001

The one I posted is more recent and looks more serious given that Frontiers is not a great journal.

#1002

I think dementia is a tough nut to crack. There is a definite link for high LDL to dementia. Low LDL being linked to dementia seems a bit off.

I would assume that very low LDL levels mean one of two things: 1. The patient is diseased. Or 2. The patient is lowering their LDL in response to earlier detected high levels.

I think it’s very rare for individuals like us to proactively lower LDL without prior high LDL which may have started the dementia ball rolling.

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#1003

I agree. We know that above 116 mg/dL the risk of dementia is increased (see the recent Lancet paper: Dementia Prevention - 2024 report of the Lancet standing Commission - #5 by adssx ).

Below 116 mg/dL it’s unclear. Dementia also covers several conditions: Alzheimer’s, Parkinson’s dementia, LBD, vascular dementia, etc. The optimal lipid levels might be different for each of these conditions. High LDL might also be a reaction of the body to protect the brain from a dementia process that has started :man_shrugging:

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#1004

For AD we have this recent good quality paper. As noted by the authors:

In addition, we found that circulating APOB (but not LDL) increases risk for AD. This finding for APOB in relation to AD conflicts with that by Williams et al. (2020), who sought to identify genetic support for the repurposing of mipomersen (an antisense oligonucleotide inhibitor of APOB34) for AD prevention. Like us, Williams and colleagues used IGAP GWA study data for the AD outcome source in their two-sample MR. Their study differed from ours in the construction of their genetic instrument, though. Whereas our instruments for APOB contained more SNPs, which were clumped to prevent LD, they used a principal-components-based MR method. We attempted a partial replication of our MR of APOB on AD using a substantially larger GWA study containing more than triple of the number of AD cases. Although our partial replication succeeded in the sense that the results revealed that higher levels of APOB increased risk for AD, the effect estimate attenuated towards the null. Future MR studies of AD, ideally with a larger number of clinically defined cases (and not including IGAP cases) are needed to confirm whether the relationship between APOB and AD is causal.

The distinction between LDL and ApoB might explain some conflicting findings?

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#1005

I have tried this and it is not nearly as effective as when the statin is added.
It may be good enough if you already have low LDL levels and you just want to lower it a little bit more.

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#1006

How do you lower ApoB preferrentially, without affecting LDL quite as much? So if the ApoB is the problem, and you want to smash that down without also crushing LDL below the safety zone?

#1007

I don’t think you can lower ApoB only. I only mentioned that as a source of complexity.

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#1008

That would imply a goldilocks solution, where you want to lower ApoB up to a point, but not further, and it’s basically a tradeoff. Who knows, maybe one day there will be more narrowly focused and less blunt interventions.

I think an example of this is the Lp(a) story - a very nasty particle, which actually goes up with statin use - but we are in a tradeoff situation where statins are still a net positive despite the bad impact on Lp(a) (and diabetes etc.!). However, now there are several drugs in development that zero in on Lp(a) specifically - as someone who has very high Lp(a), I can’t wait.

So what I’m saying is that perhaps there are more narrowly tailored intervention that can affect the other constituents of ApoB, without affecting LDL quite as much.

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#1009

I don’t know how you could selectively reduce ApoB without reducing LDL, since LDL contains ApoB. You’d have to find other targets on “bad” lipoproteins that aren’t shared with LDL (but that also have ApoB) and go after them separately.

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#1010

Do you have a link to the full article?

#1011

FYI, if anyone is interested in cholesterol levels of children (TC, LDL, HDL, Triglycerides), here’s an excellent paper.

Children up to 12 years old have a very low blood cholesterol level in general.

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#1012

Maybe it’s something about size / volume of cholesterol per particle….

I know the detailed NMR (or what they are called) cholesterol reports and Boston Heart reports have a lot of focus on that

#1013

I read the values, they should be verified by other databases since could be shifted upwards in that population from India. My son who is 21 has a TC= 115 and an LDL = 61 mg/dL, notwithstanding being overweight. Another overweight friend of him has a TC of 113, same age.

Anyways. the article illustrates well the rising trend of cholesterol with increasing age.
Newborns with 24±11 mg/dL is pretty eloquent, in a timespan when brain development his highly accelerated.

Philosophically, it’s interesting to remark that this is one of the body control systems which appears to break down pretty quickly.

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#1014

Colchicine by itself can cause myopathy in humans (hopefully dose-dependent?), but this appears to be exacerbated by rapamycin and simvastatin.

Came across this today when doing an AI-assisted search for effects of colchicine on adaptations to exercise:

Hopefully the low dose used for CVD event reduction will minimize the risk. I’m not currently taking rapamycin or a statin, but those of you who are might want to tread carefully.

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#1015

That is scary. I’ve been taking one day off of colchicine when I do Rapa but only because of the GFJ. Still have noticed nothing in the way of a side effect except that my tinnitus is nearly gone. I’ll extend it to 3 days off (every two weeks), thanks.

#1016

“serious drug–drug interactions are rare and no more frequent than placebo, including in patients taking statin therapy”

That’s good to see. I imagine if there’s a real-world effect of combining with pulsatile rapamycin (and/or with rapa + statin) we’ll start hearing about it soon, since colchicine will likely become a lot more popular in the coming months.

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#1017

Did this become mitigated when you started colchicine, or something else (or other combination)?

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