Just as I was about to order my new supply of glucosamine sulfate—a supplement I’ve been taking faithfully for over thirty years ever since I read Jason Theodorakis’ best-seller The Arthritis Cure—a story dropped that gave me pause.
It was all over the media, with headlines like: “Millions Take This Joint Supplement but Scientists Found a Concerning Alzheimer’s Link”.
The usually-reliable Science Daily proclaimed: “Popular joint supplement glucosamine linked to faster Alzheimer’s progression”.
They summarize the study’s findings as follows:
“A major study suggests glucosamine, a popular supplement for joint pain, could be linked to faster progression from mild cognitive impairment to Alzheimer’s disease, and uncovered biological clues that may explain why.”
While I’m always willing to shed long-cherished beliefs in the face of new—even unwelcome—evidence, I wasn’t going to jump to conclusions based merely on news reports which often distort the findings of original research—often more nuanced or just plain wrong.
So, I drilled down and read the study on which the stories are based.
It’s entitled “Hyperglycosylation is a metabolic driver of Alzheimer’s disease” and it’s published in a high-impact journal, Nature Metabolism. It’s a real comprehensive study, meticulously laying out, in stepwise fashion, from test-tube, to mouse models, and finally to human subjects, the molecular biology that may underlie a risk from supplements like glucosamine.
First, a word about glycosylation. It’s the biological process by which sugars attach to proteins and damage their function. Chefs take advantage of an accelerated version of glycosylation—the “Maillard reaction”—when they apply sugary marinades to slow-cooked meats to yield barbecue delicacies.
A slower version occurs in the body, and it’s thought to be a major aging pathway. Dysfunctional glycosylated proteins cause skin discoloration and wrinkles when they disrupt collagen. Internally they inflict damage on organs.
Once, lecturing to doctors at a medical conference, I flashed a PowerPoint slide of the ravaged visage of Rolling Stones front man Keith Richards. That’s glycosylation on speed-dial, hastened by years of dissipation!
When you take a HgbA1c blood test to measure your average blood glucose over the past months, you’re measuring glycosylation—it’s a test that measures the degree of cumulative glycosylation of the protein hemoglobin in your red blood cells. Over time, high sugar in your bloodstream comes into contact with hemoglobin, latches onto it, and damages it.
Turns out HgbA1c is a proxy, using a simple blood draw, of the state of glycosylation of all the essential proteins within your body. We’re all being slowly glycosylated, it’s just a matter of degree. Diabetics with high blood sugar are notorious for their accelerated aging, with premature brain, nerve, eye, heart, and kidney degenerative changes—even advanced wrinkling and skin discoloration.
So, the first part of the Nature Metabolism study meticulously recites and amplifies the evidence that glycosylation is a major driver of brain deterioration.
If the researchers had quit there, the take-home message would’ve been: “Control your blood sugar carefully to preserve your brain.” That’s essentially the message of Dr. David Perlmutter’s best-seller Grain Brain. Perlmutter argues for radical restriction of carbs to achieve a HgbA1c in the low fives or less (mine is 4.9). He cites evidence that erstwhile “borderline” HgbA1c’s of 5.6-6.2—not yet meeting the threshold of diabetes—significantly increase the risk of cognitive decline for each 0.1 increment.
But the researchers went further. They suspected that consumption of a sugar amino acid—glucosamine—might contribute to brain glycosylation. Many things get broken down before they reach the brain, or else can’t cross the restrictive blood-brain barrier, but glucosamine is known to have brain uptake.
This notion that nutrients we consume can contribute to our glycosylation burden is not new. Eating glycated proteins is recognized as harmful because they introduce advanced glycation end products (AGES) into the body. Aptly-named AGEs are compounds formed when sugars bind to proteins or fats. While the body produces some AGEs naturally, consuming them—especially through processed or high heat-cooked foods—accelerates systemic damage, disease, and aging.
AGEs find their way into our diet via high heat-processed baked goods, meats, and ultra-processed foods.
The Nature Metabolism researchers fed mice specially bred to provide a mouse model of Alzheimer’s the equivalent of human consumption of 2500 milligrams of glucosamine per day. That’s a bit much, because humans taking glucosamine usually top out at 1500 mg per day, but that’s OK, I’ll let it slide.
Indeed, the Alzheimer’s-prone mice consuming glucosamine developed the mouse equivalent of dementia at an accelerated rate, and their post-mortem brains reflected higher degrees of glycosylation, supporting the hypothesis that glucosamine exerted toxic effects on their brains. This is good science because they not only demonstrated harm but also provided a mechanistic explanation for it.
Then, they looked at humans. And, indeed, they found that Alzheimer’s sufferers who took glucosamine died on average 25% sooner than those who took no glucosamine. Whoa!
But I have some quibbles with this finding. First, I’m suspicious of the methodology by which they garnered information about glucosamine usage. They polled patients as to whether they used the supplements and then corroborated these reports via “doctors’ notes” in electronic health records. Self-reports are notoriously inaccurate, and doctors seldom take time to accurately catalog their patients’ supplement use.
Yet another problem: Subjects who were classified as taking glucosamine were not differentiated according to the dosage of glucosamine they were taking (products vary enormously), or how faithfully or sporadically they were taking it. Was it 600 milligrams, 1200, or 2400? Did subjects skip days? It was all or nothing.
Unfortunately, there’s no glucosamine blood test. Unlike supplements like vitamin B12, iron, vitamin D, or Omega-3 fatty acids, we have no way of measuring glucosamine levels to assess actual consumption. We have only the word of patients’ caregivers (because Alzheimer’s patients have no recall whatsoever) and spotty records of doctors to corroborate their use.
That’s the Achilles’ heel of this study, otherwise rigorous. For me, it’s a deal-breaker.
Worse yet, glucosamine use might simply be a proxy for the presence of painful arthritis. It’s known that inflammation is a prime driver of neurodegenerative changes. Inflammation that affects joints inevitably contributes to the brain burden of inflammation. If you’re not worried about your joints, why bother taking glucosamine?
I’m skeptical that, as the researchers claim, fully 8% of Alzheimer’s patients take glucosamine. It’s so hard to get Alzheimer’s patients to take supplements altogether that there must have been a strong impetus, beyond general prevention, for them to faithfully swallow the big capsules or tablets. There are so many other supplements to prioritize that might support brain health. Somehow it doesn’t make sense.
Finally, using death as a proxy for accelerated Alzheimer’s progression is misleading. Earlier death in these patients is a disturbing signal, but it might not be due to Alzheimer’s. A preferable future study—ambitious in scope—would periodically test the cognitive function of verified glucosamine takers compared to controls, over years and decades.
Still, a funny thing happened when the researchers studied patients with MCI (mild cognitive impairment). MCI is thought sometimes to herald Alzheimer’s, but only a small minority of MCI patients go on to develop full-blown Alzheimer’s.
The MCI patients who took glucosamine didn’t experience accelerated death rates. Instead, they were said to be 25% (why always that suspiciously round number 25%?) more prone to progression to Alzheimer’s, but since only 5% of MCI patients actually progress to Alzheimer’s, the difference here, when expressed in absolute terms is small: 5% vs. 6.25%, calling into question the statistical significance of the actual difference in a small sample size of subjects.
This is a very big deal, because even “authoritative” sources like Science Daily mis-reported the study. They said, “Researchers found a 25% higher likelihood of developing dementia among glucosamine users”, which was not the case.
It makes it sound like normal people who took glucosamine supplements had a higher likelihood of Alzheimer’s—clearly not what the study demonstrated.
In fact, confronted with the paradox that Alzheimer’s patients, but not MCI patients, conclusively suffered adverse effects from glucosamine, they circled back to mice.
What they found was that wild-type mice, without Alzheimer’s susceptibility, consumed glucosamine with no adverse effects on memory. Moreover, they write: “Strikingly, glucosamine supplementation did not result in hyperglycosylation in WT [wild-type] mouse brains.”
The study authors admit in their discussion section, that “Our data suggest that glucosamine does not clinically worsen outcomes in individuals with MCI, but is associated with worse survival in patients with AD/ADRD [Alzheimer’s and Alzheimer’s-related disease]”.
They theorize that something about Alzheimer’s may make sufferers uniquely susceptible to the glycosylating effects of glucosamine—but ordinary takers seem resilient.
So, what’s the real take-home? Even if this study has many flaws, it does uncover a potential danger signal that should be heeded, pending additional research. Subsequent studies might eventually exonerate glucosamine: Remember the short-lived flaps over choline and TMAO? Melatonin and heart failure? Fish oil and atrial fibrillation? And countless other supplement “perils” that didn’t withstand the test of time or the light of scientific scrutiny.
But, for the time being, heeding the “precautionary principle”, it might be prudent to forego glucosamine for patients with documented Alzheimer’s. That might extend, hypothetically, to high-risk patients with the so-called “Alzheimer’s gene”—ApoE4.
But for older individuals merely concerned about memory—the “worried well”—it doesn’t make sense to forego the established joint-protective and anti-inflammatory benefits of glucosamine.
The way academic science works, this study will be pored over by eminent researchers and picked apart. Its deficiencies, and countervailing research, will spawn extensive discussion and additional studies, to confirm or refute its conclusions.
Even with this mere whiff of controversy, the glucosamine market will certainly take a hit. That poisoning of the well for earnest supplement users is unfortunate. Paradoxically, we heedlessly take aspirin and Motrin despite the fact that thousands suffer bleeding ulcers; Tylenol when hundreds experience liver failure; and addictive anti-anxiety drugs that hasten cognitive decline for millions. But glucosamine is now Public Enemy #1?
Meanwhile, undaunted, I went ahead and reordered my six-month supply of glucosamine/chondroitin. Armed with the facts, what will you do?
