Ok, I think I understand you now.
Each person will likely have a different decision on how to weigh the tradeoff. (Just thought it important that we all understand that it likely is a tradeoff).
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ISWYDT 
You are 40 years old, going about your business, and feel absolutely fine. But you grow concerned about cardiovascular disease. So you go see your doctor, and she hooks you up to some devices. They say you have elevated blood pressure and apoB. Perhaps your sodium, saturated fat, or purine intake is too high and are causing (previously unknown to you) elevations in your BP and apoB. But you feel fine, and you will likely continue to feel fine for decades: at no point will you āsenseā that your BP and apoB are too high. Is that something you should lose sleep over?
Youāve just listed them.
Of course, you could look for alternative pleasures, including the new wave of increasingly-credible nonalcoholic wines.
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I think this is more what Iām getting at, and how the glass of wine ties into the rest of the thread. When someone is overall very fit and healthy and has what would be very good measures (ApoB or otherwise), when do the tradeoffs with your personal comfort level - whether itās discomfort with taking statins or discomfort with giving up your glass of wine become worth it to achieve that last little percentile of health (like taking your ApoB from 58 to 30 or lower). Thereās no (or little) disagreement on the science, perfect is better, but when you are already very good and itās a small statistical improvement, you have to weigh that against your comfort level.
Not trying to derail this thread but from this article about a recent meta-analysis that said any alcohol is bad for your health, I quote:
" Stockwell says deciding whether and how much to drink is a personal choice. Based on his research, Stockwell estimates that someone who drinks one alcoholic beverage per day shaves about five minutes off their lifespan with each drink, and the losses compound at higher levels of consumption. Whether thatās an acceptable tradeoff, Stockwell says, is up to the drinker."
https://time.com/6267540/alcohol-premature-death-risks/
So one glass of wine per day would decrease your lifespan by 30 hours in a year. Iām 70 now, so by the time Iām a hundred, I would have decreased my lifespan by 38 days. Is that worth losing sleep over? For meā¦no.
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And here you have itā¦a scientific study: Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster - PMC
" Our aim was to study the effect of red wine consumption on longevity-related genes in controlled human populations, such as cloistered nuns.The major shortcoming for nutritional intervention studies, especially those on nutrients like wine, is lifestyle. It is likely that individuals with moderate wine consumption also engage in other healthy habits, including stress control. Probably, the only populations that can be strictly controlled are monks and nuns who live in the same environment, with the same routines, and with controlled diets.It is important to underpin that the catholic nuns enrolled in this study had not drunk red wine in the previous two years. We did not use dealcoholized red wine in human studies because of the very low palatability. Our nuns refused to take the non-alcoholic red wine."
Conclusions
The major conclusions of our study are that moderate wine consumption increases the expression of key longevity-associated genes like p53, sirtuin1, catalase, and superoxide dismutase in humans. It also significantly increases longevity-associated gene expression and longevity itself in flies, thus showing that the effects are maintained across the animal kingdom. No serious unwanted side effects were observed.
ā¦ with a short-term, unvalidated surrogate outcome in blood cells
But You missed the main point - āWe did not use dealcoholized red wine in human studies because of the very low palatability. Our nuns refused to take the non-alcoholic red wine.ā Who said the penguins donāt have good taste?
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Looking at this study again (by US NIH + Oxford researchers in the JACC, so most likely high quality), Iāve just noticed the figure: although it didnāt reach statistical significance it seems that statins may be good for amyloid but bad for Lewy body dementia. (while PCSK9i are neutral for both) Do I understand things correctly? So it might explain the contradictory results in studies around statins and cognition. Could it be that for instance statins reduce the risk of vascular dementia and AD but increase the risk of PD and PDD/DPB/LBD? (pure guess) So they would be overall neutral on ādementiaā but with different outcomes by subtype, and because itās so hard to diagnose the subtypes (and people often have mixed dementia with all pathologies present) it could blur the results in studies. Please correct me if Iām wrong.
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First, an important caveat to MR studies is that they can reflect influences of the genes during development, which donāt apply for drugs that are initiated during midlife. Low HMGCR activity could plausibly restrain myelination or other effects on the rapidly-growing fetal brain in ways that are irrelevant in the very slow turnover state in mid- and late-life.
We use MR best as a proxy for clinical trials we canāt run. Weāve run lots of clinical trials with statins: thereās no āthereā there.
Second, in an MR of ā¼740,000 participants, the CIs for both amyloid deposition and DLB extend so far on both sides of 0 that you can in any case conclude with substantial confidence that thereās no āthereā there on its basis alone.
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Wouldnāt the interpretation be the opposite based on the graph?
However, I agree with @RapamycinCurious that speculating is challenging given the lack of statistical significance in the associations.
Personally, if genetically predisposed to any type of dementia, I would opt to avoid statins though.
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Investigating MR with cognition is a futile effort. It is a highly polygenic trait so a single genes have very small effects in either direction. The good thing is that almost nothing will affect cognition in the long term in a clinically significant way. Including PCSK9 inhibition and HMCGR, even with lifelong inhibition.
All-cause dementia and mortality is interesting however.
I agree (I didnāt know before btw, learned this thanks to Neo in another thread; I love this community where I learn something new every single day!)
For PD, we have RCT + MR + longitudinal + observational studies showing a decline with statins. But thatās in PD. In healthy individuals, RCTs donāt show anything indeed. But given the link between PD and LBD I found it interesting that this paper looked at LBD. Given the time needed for NDDs to develop and the specific demographic (old people), this cannot be captured by short RCTs on the general population. Do we have RCTs of statins on people with MCI? Iām pretty sure that people with MCI are excluded from most trials because they cannot follow the protocol, and it would be a mess to have them in. I could only find these trials:
- Trial of Simvastatin in Amnestic Mild Cognitive Impairment (MCI) Patients (SIMaMCI): Unknown statusā¦
- Evaluate the Effect of Atorvastatin on Cerebrovascular Reactivity in MCI: Results next year?
- Statins In The Elderly (SITE): results soon? (quite a crazy trial: itās about stopping statins in people above 75yo and seeing the results 3y laterā¦)
- A Clinical Trial of STAtin Therapy for Reducing Events in the Elderly (STAREE) (STAREE): results in 2026?
- Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults (PREVENTABLE): results in 2027?
Regarding the STAREE trial, the authors noted in early 2023:
(source)
Yes, 740k is massive. But at the end for LBD itās 2,591 cases: 4,027 controls. And people with LBD are often undiagnosed or misdiagnosed (source). So there are probably many LBD cases that are not LBD but another kind of dementia or depressive disorder while there might be many LBD cases among controls. How many? I donāt know but thatās why (and combined with the signal for PD mentioned above) Iām not āas strictā in terms of CI and Iām looking for ādirectionsā.
Hmā¦ They write āConversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: ā0.082; 95% CI: ā0.16 to ā0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = ā0.18; 95% CI: ā0.35 to ā0.014; P = 0.03).ā and āHowever, our finding of concurrent improved memory performance associated with the HMGCR instrument highlights the complexity of the HMGCR-cognition relationship.ā and for these, we can see on the image that for statins (HMGCR): cognitive performance is on the left of the axis, memory performance is on the right, reaction time is on the right, but they used āreaction time DEFICITā (why on earth did they do that?!), and total cortical surface area is on the left. So I understood that left = negative beta = ābadā. Did I misunderstand? 
Because then they write: āgenetic inhibition estimates for PCSK9 were on the beneficial side of null with regression coefficients in the direction of reduced AD progression score, lower amyloid deposition levels, and lower LBD riskā And for PCSK9 they give (Table 2):
- Disease progression score: 0.0086 (ā0.16 to 0.17)
- Cerebral amyloid deposition: ā0.0038 (ā0.55 to 0.55)
- Lewy Body dementia: ā0.018 (ā0.51 to 0.48)
āon the beneficial side of nullā seems quite a big leap of faith but anyway, it means that negative beta for LBD is protective? So statins potentially protective?
Help needed if anyone knows how to understand the resultsā¦
Btw, from last week at the Pan American Parkinsonās Disease and Movement Disorders Congress. So itās not only about me/us a few longevity weirdos here. Some serious folks also have doubts: https://twitter.com/AlbertoEspay/status/1756678599438995951
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Yes, both psk9 and hmgcr inhibition genes associated with lower mean lewy body disease risk. But without any statistical significance. So potentially statins still could be protective or harmful or neutral
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Thanks. Still interesting because another recent MR (preprint) showed that statins may be neutral wrt PD risk but might shift from the freeze of gait subtype to the tremor subtype. Maybe one of these subtype is more associated with cognitive decline than the other.
Anyway, thereās a link between lipid lowering drugs and cognition and itās probably not as simple as āstatins goodā or āstatins badā (does it depend on your BMI? Diabetes status? Genes? Age? 
). I hope the ongoing trials will clarify the picture. I contacted the lead clinician behind the statin cessation study (Statins In The Elderly (SITE)): results expected āthis summerā. Wait and seeā¦
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Obicetrapib might come to market the latter part of this year if approved for reducing LDL, based on two phase 3 trials:
āHeFH and ASCVD can be devastating diseases which, if inadequately addressed, can result in myocardial infarction, cerebral infarction, or cardiovascular death,ā said John Kastelein, M.D., Ph.D., FESC, Chief Scientific Officer of NewAmsterdam. āIt has become increasingly clear that lower levels of LDL-C are directly correlated with a reduced risk for major adverse cardiovascular events. With obicetrapib, we aim to deliver LDL-C reductions that are substantially better than currently available non-statin oral therapies, in a convenient, tolerable formulation. We are pleased to have both BROADWAY and BROOKLYN, the two pivotal Phase 3 trials necessary to support a potential LDL regulatory filing, fully enrolled and look forward to reporting data from both studies in the second half of 2024.ā
Our product candidate, obicetrapib, is a next-generation, oral, low-dose CETP inhibitor that we
are developing to potentially overcome the limitations of current LDL-lowering treatments. We believe
that obicetrapib has the potential to be a once-daily oral CETP inhibitor for lowering LDL-C, if
approved. In our Phase 2b ROSE trial, obicetrapib demonstrated a 51% lowering of LDL-C from
baseline at a 10 mg dose level on top of high-intensity statins. In all three of our Phase 2 trials, TULIP,
ROSE and OCEAN, evaluating obicetrapib as a monotherapy or a combination therapy, we observed
statistically significant LDL-lowering activity combined with generally moderate side effects and no
drug-related, treatment-emergent serious adverse events (āAEsā). Obicetrapib has demonstrated strong
tolerability in more than 600 patients with low or elevated lipid levels (ādyslipidemiaā) in our clinical
trials to date. Obicetrapib is also expected to be relatively low in cost to manufacture compared to most
other branded LDL-lowering therapies on the market with high efficacy. We believe that the estimated
low cost of goods for obicetrapib will enable favorable pricing and position it to significantly improve
patient access to a high efficacy LDL-lowering therapy compared to existing non-statin treatments.
Furthermore, we believe that obicetrapibās oral delivery, demonstrated activity in low doses, chemical
properties and tolerability make it well-suited for combination approaches. We are developing a fixed
dose combination of obicetrapib 10 mg and ezetimibe 10 mg, which we believe will demonstrate even
greater potency
We believe that CETP inhibition may also play a role in other indications by potentially mitigating
the risk of developing diseases such as Alzheimerās disease or diabetes. Evidence suggests that
cholesterol accumulation in the brain is a precursor to Alzheimerās disease. For example, rodents lack
the CETP gene and are resistant to Alzheimerās disease. In early preclinical studies, when the human
CETP gene is knocked into a mouse, the cholesterol content of the mouse brain was observed to increase
by 25% and when combined with the gene for the amyloid precursor protein, hypothesized to be a driver
of Alzheimerās disease, the risk of developing Alzheimerās disease may greatly increase. In a preclinical
study, we observed that CETP inhibition promoted cholesterol removal from the brain and improved
cognition. We commenced a Phase 2a trial in early 2022 in patients with early Alzheimerās disease and
the apolipoprotein E4 (āApoE4ā) mutation to evaluate the pharmacodynamic and pharmacokinetic
effects, safety and tolerability of obicetrapib. Clinically demonstrated anti-diabetic benefits have been
observed with CETP inhibition in Phase 3 CVOTs that, if seen in obicetrapib, would differentiate it from
current treatment alternatives, especially statins. We are planning preclinical studies to examine the
potential of obicetrapib for patients suffering from diabetes and have included the onset of diabetes as
an endpoint in our PREVAIL CVOT, as measured by AEs indicating Type 2 diabetes, initiation of anti-
diabetes medication after confirmed diabetes diagnosis or high levels of hemoglobin A1c and fasting
plasma glucose.
https://ir.newamsterdampharma.com/static-files/91cc75c7-08db-4696-9bd6-c05bb01762ed
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Super interesting. This preprint MR confirms the potential for dementia prevention: https://www.medrxiv.org/content/10.1101/2023.11.03.23298058v2
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Hopefully we can see their 2023 annual report soon?
Also promising Lp(a) it seems (even if I know there are other meds for that also reading out soon that look promising).
Obicetrapib 5 mg reduced ApoB by 24.4%, non-HDL by 38.9% and Lp(a) by 33.8%, whereas obicetrapib 10 mg reduced ApoB by 29.8%, non-HDL by 44.4% and Lp(a) by 56.5% (P for all < .0001), Davidson and colleagues found.
And also beyond Lp(a) and Apo B effects - increase in HDL (that they are not focusing communication on as people are skeptical about past attempts to HDL upā¦)
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I would be surprised if that didnāt publish and pass peer review. It is after all the scientists at NewAmsterdam Pharma like Kastelein.
I donāt understand why they didnāt look at other dementia like for Alzheimerās, instead specifically PD dementia and LBD. The effect on PD dementia was nice though.
Yes great team so canāt wait to see it published. For AD they write: āGiven the observed APOE4 interaction with CETP, and the absence of APOE4 stratified GWAS we did not explore associations with AD.ā
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Great, I was worried for a second. So far this drug seems very promising. CETP target also have a bunch of old papers from longevity researchers like Barzilai.
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Whatās the gist of the longevity impact (outside of cardiovascular)?
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