Repurposing Zetia: How a heart drug may wind up protecting the brain

A few years ago, I started taking the cholesterol-lowering drug Zetia (ezetimibe). My LDL cholesterol was high and I’d already tried and discontinued the usual first-line statin drug therapy, unhappy with some not uncommon statin side effects: fatigue, slight brain fog, and mild muscle aches. The Zetia experiment didn’t last long. It produced some unpleasant GI side effects, again not uncommon, so I dropped it and resolved to do better limiting the saturated fats in my diet, with intermittent success. When I worked at it assiduously, my LDL would get below 120, but it was hard to maintain that discipline all the time.  Giving up cheese and meat completely wasn’t a lifestyle choice I was willing to make – I grew up in an Italian household!

That was then. We now have a growing body of evidence  that makes an intriguing case for Zetia as a drug capable of slowing down brain aging, specifically, reducing the risk of Alzheimer’s disease.

Probably the most eye-opening study was a 2024 study that analyzed over 900,000 patient records and determined that Zetia users developed Alzheimer’s disease over seven times less frequently than the non-users.

The usual caveats apply here. This was an observational study demonstrating correlation, not causation – in other words, we don’t know for sure the drug was responsible for the lower incidence of disease. And, keep in mind, that impressive sounding eight-fold lower disease rate represents a reduction in relative risk. In absolute risk terms, the Zetia group was roughly 0.7% less likely to develop AD than the non-Zetia group. I should also add, not all the observational studies have returned positive results.

Still, this data jibes with a larger body of animal and cell culture research that suggests how Zetia may protect our brains. When Zetia was approved as an LDL-lowering drug in 2002, it was known that it targeted a protein in the gut that blocked the uptake of dietary cholesterol. Lowering cholesterol levels by itself protects brain function. But while many clinicians, me included, had assumed that the drug worked only in the gut, in fact, it’s absorbed systemically and, the evidence suggests, can even cross the blood-brain barrier. That explains how Zetia seems to be able to affect any number of aging pathways, especially those that directly affect the brain. 

In mouse models mimicking dementia, ezetimibe reversed memory deficits, improving performance in maze tests. It curtailed oxidative stress, a cellular rusting process that damages brain tissue, and restored antioxidant defenses like glutathione. Similarly, in rats with induced Alzheimer’s-like pathology, the drug diminished amyloid plaques and tangled tau proteins— hallmarks of AD—in key brain regions such as the hippocampus and frontal cortex. The research also showed that in animal brains, ezetimibe preserves cholinergic signaling—essential for memory—by inhibiting an enzyme that breaks down acetylcholine. To top it off, it promotes higher levels of growth factors like IGF-1, associated with better cognition in the elderly.

In sum, this is promising evidence that Zetia may become another example of a drug that becomes far more valuable when it’s repurposed to address health conditions other than the one it was approved for. Consider the case of the SGLT2 inhibitors which I wrote about in an earlier post -- often-overlooked second-line diabetes drugs now showing great potential as a longevity-enhancing therapy. Or rapamycin, long approved to lower the risk of organ rejection in transplant patients, although concerns remain about side-effects and long-term safety when it’s prescribed as a longevity drug. 

Clinically-speaking, where does this leave us with ezetimibe? We don’t have any evidence that the drug works as well as the statins for helping to prevent heart attacks, only one randomized controlled trial, on Japanese elders, that showed a moderate effect. So, no one is suggesting that we switch out statins for ezetimibe to protect cardiac health. (It remains a good plan B for the statin-intolerant.) And I, for one, don’t think we yet have sufficient evidence on the Alzheimer’s front to begin prescribing the drug to any and everyone on the chance it may prove effective against AD. 

(That’s the double-edged sword of re-purposed drugs. They’re readily available to be prescribed “off-label” but, because they’re already been patented, there’s no economic incentive for the pharmaceutical industry to bankroll hugely expensive RCTs to measure the efficacy of the drugs to combat other diseases. Best case scenario: Pharma comes up with a patentable analogue of ezetimibe and pins down its AD-fighting properties.)

However, for people who are at higher risk for developing AD, the risk/reward calculus changes – the greater the likelihood of benefit, the more risk you can tolerate. Let’s say a genetic test reveals you have the relatively common “single-copy” (heterozygous) gene mutation, APOE4, which increases your risk of AD two-fold. I think Zetia should be on the table, and if you’re already taking a statin, then adding it will only increase the LDL-lowering effect. If you have the much rarer double APOE4 mutation, increasing AD risk by as much as 15-fold, then I say, frankly, why not?

After decades of AD research aimed at a single target – reducing amyloid plaque – we have a grand total of one FDA-approved AD drug that meaningfully slows the progression of AD, Leqembi, wildly expensive with potentially lethal side effects. So, if you can manage the possible Zetia side effects – GI upset, muscle and joint pain, in more serious cases, break-down of muscle tissue – the pay-off could be significant.   

And genetic tests are far from the only diagnostic option. You could, for example, take cognitive performance tests at regular intervals, to detect if you’ve suffered any  concerning slippage. Where early dementia is suspected, a brain MRI can reveal greater-than-normal brain volume shrinkage (all brains shrink with age), a telltale AD sign. Not only can tests like these suggest whether starting an ezetimibe regimen makes sense, they can tell you whether, over time, it’s doing any good. If not, drop it. (The start-up NeuroAge Therapeutics offers a kind of diagnostic one-stop-shopping, a full battery of tests to measure brain aging.)

As for me, I’m considering going back to Zetia for another “n-of-1” trial. I carry the single-copy APOE4 mutation. If I’m able to discern that the drug is having a  significantly positive impact on my brain aging, I’m pretty sure I can accept the occasional digestive upset.

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Akshatha Ganne, et al. Ezetimibe Lowers Risk of Alzheimer’s and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction. Aging Biology 2024. June 26, 2024. DOI:https://doi.org/10.59368/agingbio.20240028

Dalla Y, Singh N, Jaggi AS, Singh D, Ghulati P. Potential of ezetimibe in memory deficits associated with dementia of Alzheimer's type in mice. Indian J Pharmacol. 2009 Dec;41(6):262-7. doi: 10.4103/0253-7613.59925. PMID: 20407557; PMCID: PMC2846500.

Yasuvoshi Ouchi, et al. Ezetimibe Lipid-Lowering Trial of Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial. Circulation Aug. 22, 2019. Volume 140, Number 12. doi.org/10.1161/CIRCULATIONAHA.118.039415