There has recently been much hullabaloo about THIS ARTICLE suggesting that ezetimibe, a cholesterol absorption inhibitor, may have some protective effects against Alzheimer’s Disease, which I believe is ultimately a metabolic and lipid disorder (Check out this Podcast episode where I discuss Cholesterol in the Brain HERE). Nick Norwitz, who is younger, shorter, and a million times more famous than me, recently made a provocative video about this concept (On a side note, I think Nick is an impressively prolific and intelligent individual. Since he’s one of the few people on this planet who, from what it seems, actually loves the elegance of science and biochemistry as much as me, I’m surprised our paths have never crossed). But interestingly, this actually isn’t the only time that ezetimibe, which is sort of an “unsung hero” in the toolbox of lipid-lowering therapy, has been proposed as a candidate for mitigating the fearsome tide of neurodegenerative disease.
Briefly, ezetimibe acts on Niemann-Pick C1-Like 1 (NPC1L1) to inhibit cholesterol absorption at the intestinal brush border (gut) and the hepatobiliary (Liver-Bile Junction) interface. Essentially, there is a Ticket Taker to the Cholesterol Party in the gut, and ezetimibe makes your Ticket Taker more effective at discriminating rather than letting ALL the Cholesterol Characters in…and this results in you pooping out more cholesterol. Put another way, if every ApoB particle (like an LDL particle) is a mailman, it reduces the amount of spam mail and coupons that the mailmen have to deliver; you’re just going to throw that stuff away anyhow. But now you need less mailmen to deliver the cargo, so you’ll get a decrease in LDL particles as LDL receptors are upregulated.
Ok, but we’re talking about the BRAIN, and historically it has been thought that ezetimibe acts locally and doesn’t cross the blood-brain-barrier (BBB)…but does it???? Short answer is that this hasn’t been rigorously studied, but there are two somewhat compelling reasons why it COULD cross the BBB.
- Size does matter, and molecules smaller than 600 daltons can typically cross the BBB…ezetimibe is a little over 400 daltons.
- Lipophilic (fat-loving) molecules tend to more readily cross the BBB, and ezetimibe is lipophilic.
BUT…in order to effectively cross the BBB, the drug needs to NOT be shackled to another plasma protein (which typically happens with ezetimibe), so the degree to which it’s getting into the central nervous system (CNS) might be limited.
ADDITIONALLY, ezetimibe is GLUCURONIDATED, which increases its hydrophilicity, in its Phase II metabolism, and this would theoretically impair traversal into the brain. And there is another Blood Brain Barrier Guardian called p-glycoprotein which stops substances from getting into the CNS…and ezetimibe is a substrate for p-glycoprotein. Although ezetimibe makes your Ticket Taker in the gut more choosy, the drug itself might be on the Watch List and be detained if it attempts to journey to the brain.
And ezetimibe could be influencing autophagy (cellular housekeeping) in the brain via direct mechanisms. Some of the mechanisms, that have been suggested are via AMPK, a master nutrient sensor, and Nrf2 (which you could say shoots down oxidative stress and toxic processes with Nerf bullets). But could these and other neuroprotective processes be INDIRECTLY modulated by ezetimibe? (Sort of like Klotho, which is a “Longevity Darling” that is too large to cross the BBB, but seems to direct Brain Traffic in a beneficial way). I think it’s plausible, and there are many theoretical candidates, including:
-There could be involvement of ezetimibe in Gut-Brain axis signaling.
-Ezetimibe could indirectly be influencing total-body glucose homeostasis and the ubiquitous “Control Your Insulin, Control Your Life” axiom, particularly in regards to freeing up hexokinase, the first enzymatic step in glycolysis, to function unimpeded. (This is mentioned in the article Nick referenced…just like “6-7” is indicative of Brain Rot in our current adolescent population, “14-3-3” leads to Brain Rot and amyloid/tau pathology if it’s bound to hexokinase). Substrate utilization in the brain is of critical importance across the lifespan.
-Ezetimibe could be shifting the composition of bile acids and fatty acids, which are known to act as potent signaling molecules that alter various nuclear transcription factors both centrally and peripherally.
-And specifically, ezetimibe reduces deoxycholic acid, which is a secondary bile acid associated with cognitive impairment and Alzheimer’s disease in various patient populations. Perhaps ezetimibe reducing deoxycholic acid has some important implications in preservation of cognition.
So anyway, I remain optimistic that we will, in the future, have an individualized metabolic and lipid-centric framework that can ultimately make neurodegenerative disease a distant memory. And as we continue to Stay Curious, I will also Stay Curious (and optimistic) that Dr. Norwitz reaches out to me someday…I think we’d have fun😊
