Thread by @nicknorwitz

Get ready for a thread of questions about the recent ApoB shortens lifespan Mendelian randomization study, posed as my top 8 questions.

Thanks everyone in advance for their thoughts, genuinely. .@DaveKeto .@ethanjweiss .@DrNadolsky

sciencedirect.com/science/articl…

1/ How robust were the instruments? Were derived from linkage disequilibrium clumping w clumping parameters of 1 million nts, including 229 SNPs 4ApoB. Stated that tool would “not be considered weak,” Can someone explain this to the Twitter lay audience please?

2/ Building on that, while they adjusted for genetic parameters, I didn’t see anything about adjusting for medications? If they’re talking biomarker data and not adjusting for meds doesn’t the analysis appear vulnerable to healthy use bias?

3/ Irrespective of 2, we know the analysis couldn’t have been comprehensive and they were based on ‘genetically predicted ApoB.’ Therefore, is it fair to assume that the data would apply to LMHR individuals who might have (at baseline, pre-low carb) very low ApoB?

4/ Building on 2 and 3, the high-risk of CVD associated with higher ApoB is being put through a filter of a standard diet and lifestyle.

I agree that LDL participates in CVD and is necessary in atherogenesis. But necessity doesn’t imply sufficiency.

So...

4/ cont'
if you have that “rare” case in which ApoB is high but a personal exhibits excellent metabolic health and little inflammation (many LMHRs) then might not the anecdote cause more harm than the poison?

Isn’t this at least possible?

5/ Medications that lower ApoB also lower LDL. In the multivariate, latter is associated w longer lifespan and lower diabetes risk (and lower AD risk). In treating ApoB, affecting two variebles that are both important in the outcome of interest in opposite directions. Correct?

6/ Same discrepancy as seen for diabetes seen for Alzheimer’s in Supp 2-3/5. High ApoB increases risk of maternal AD, whereas high LDL appears protective. Would have been nice to see those data discussed given that T2D/AD r on the rise faster than CVD. Not Q, just an observation

7/ Specifically for .@DaveKeto… Supp figure 8… thoughts?