The theory that Alzheimer's dementia is in part caused by chronic high blood sugar, as in uncontrolled or poorly controlled diabetes, is fairly well known. The first I heard of it was in Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health by Gary Taubes. He has a whole chapter on dementia, cancer, and aging - pages 204-225 if you are following along in the hard copy - which I bought when it came out back in 2007.

Here's the theory. Hypertension, atherosclerosis, smoking, and the gene for ApoE4 increase the risk of cardiovascular disease, vascular dementia (obviously - vascular dementia is generally thought to be caused by multiple and increasing stepwise vascular insults to the brain, like little strokes or clots) and Alzheimer's dementia (which is associated with excess tau and amyloid protein build-up in the brain, so the brain starts operating rather like a fish tank that never gets cleaned). Folks with type 2 diabetes have twice the risk of developing Alzheimer's, and diabetics on insulin therapy have four times the risk.

There's a protein called insulin-degrading enzyme that does just what you might expect. It clears out insulin in the brain. It also clears out excess amyloid (at least in test tubes), so one can imagine if it were super-busy with the insulin, amyloid might get left cluttering up the joint. Unlucky mice with no insulin-degrading enzyme get dementia, and elderly people get increased amyloid in their cerebral spinal fluid when insulin is injected into their veins.

The obvious conclusion is that one wants appropriate, physiologic insulin levels so that your insulin-degrading enzyme can keep itself busy with the pesky amyloid, leaving none to form plaques. One way to achieve that is a low carbohydrate diet. Even the high-carbohydrate eating Kitavans, though, had exceedingly low fasting insulin levels (1), so a paleolithic-style diet will seem to do the trick if you don't have metabolic syndrome to begin with.

Is Alzheimer's disease increasing? Yes, absolutely. Wouldn't it be nice if we could do something about it? The National Institutes of Health convened a panel in early 2010 and determined there is no reliable way to prevent Alzheimer's.  One interestng fact must be considered - Staffan Lindeberg found no evidence of dementia or anyone who knew anyone with symptoms of dementia on the island of Kitava, who eat a paleolithic-style diet with starchy tubers, coconuts, fish, and no modern industrial foods, wheat, vegetable oil, or dairy.

So we know what Gary Taubes thinks.  Since Good Calories, Bad Calories came out, there has been quite a bit more research into the topic of metabolic syndrome and the risk for Alzheimer's dementia. And if you look at the primary sources, the results (not surprisingly) paint a less certain picture than in Gary's book.  For example, there are groups who seem to be protected from dementia by metabolic syndrome, which can be associated with hyperglycemia (2). Then there are diabetics whose brains don't seem to have an increase in beta-amyloid plaques despite insulin-degrading enzyme issues, directly disproving Gary Taubes' theory (3).  Other researchers who found that diabetes is assoicated with Alzheimer's, proving Gary Taubes' theory (4).  There's a brand new study that came out this week, showing more links between diabetes and Alzheimers. (5) And another brand new pilot study showing that intranasal insulin treatment (which would increase the ability of cells to soak up glucose) improved symptoms of dementia (6). This same study notes that folks with Alzheimer's disease tend to have lower than normal insulin in the brain than average - exactly the opposite of what you would expect in a type II diabetic, and opposite of what you would expect from Gary Taubes' theory. Finally some autopsy studies from Japan show no link between diabetes and Alzheimer's dementia (7).

How do we pull all that contradictory information together?  It's complicated.

When you try to connect dementia and hyperglycemia, you do come to some simple conclusions - hyperglycemia speeds up aging.  It's like our metabolisms in fast-forward.  Anatomic brain differences have been shown in patients with diabetes (type I and II) consistent with non-diabetic patients > 80 years old.  Also shrinkage of the hippocampus and the amygdala (these are also found to be shrunk in type II diabetes).  Patient with uncontrolled type II diabetes have worse cognitive function and memory.  Patients with more diabetic complications (suggesting poorer glycemic control) also have more cognitive difficulty.  Studies of the "oldest old" (>85 years) don't seem to show a difference between diabetic and non-diabetic populations, though.  Though at that point almost everyone starts losing weight (possibly improving diabetic control).  Alzheimer's disease is the cause of dementia in 82.5-91% of type II diabetics - which is greater than the general population.  Insulin degrading enzyme (IDE) is still important - patients with the genetic predisposition for Alzheimer's have decreased expression of IDE in the hippocampus.  There's enough interesting epidemiologic evidence and common sense plausible biologic mechanism that you do have to wonder. And it certainly doesn't hurt to keep one's blood sugar and insulin under good control for overall health and wellness.

The best hypothesis I can come up with is that a combination of the genetic predisposition to Alzheimer's (carrying the ApoE4 allele) and diabetes could put one at higher risk.  People with ApoE4 seem to have lower amounts of enzyme to clear away amyloid in the first place, so add lots of insulin, and you've got plaque city.  But hyperglycemia alone wasn't going to explain it - though everyone agrees that hyperglycemia is rotten for the brain.

So what does cause Alzheimer's?  Truth be told, a whole cascade of things played out over decades (8).  Beta-amyloid peptide is definitely a key player, but it certainly isn't the only one.  It all begins with amyloid aggregating in vulnerable areas of the brain (called plaques - and this takes years and years), followed by accumulations of tau protein (called tangles).  The plaques and tangles (when I was in residency, there was a holy war going on between different sects of brain researchers about which was more important - plaques or tangles) seem to interact with inflammatory cells in a way that the accumulated plaques and tangles finally trigger diffuse brain toxicity and neuronal death.  At the beginning, measuring amyloid can predict problems even before someone experiences the first clinical stage of Alzheimer's called "mild cognitive impairment" (MCI).  The cognitive decline seems to be triggered when tau protein increases.  So, to recap - long symptomless amyloid buildup, tau takeover, inflammation and neuron destruction.  Boom.  Alzheimer's dementia.

Researchers looking just at amyloid ran into problems.  For example, there has long been interest in developing a vaccine against amyloid - sounds awesome, right?  Zap out Alzheimer's with our own immune system!  However, by the time the amyloid has accumulated to Alzheimer's proportions, it's very unlikely that a vaccine could reverse the course of the disease.  Vaccine trials (and trials of other drugs that lower amyloid production) even showed reversal of plaque build-up at autopsy, but the patients were still demented despite zapping the plaques.   If you wanted to stop Alzheimer's by targeting amyloid, you would need to start decades earlier, and no one wants to take an experimental preventative anti-amyloid medicine without a safety track record for a lifetime  (or at least I don't!).  However, this brings up the interesting hypothesis that low-carbers, paleo diet enthusiasts, Kitavans, or anyone who avoids hyperglycemia could be preventing amyloid build-up at this long prodromal stage, thus possibly reducing risk of later Alzheimer's.

But... there are types of frontal temporal dementias in humans that involve just tau protein, no amyloid required.  Any treatment or hypothesis that is focused on amyloid is missing a big part of the picture (sorry, plaque researchers!).  If you are looking to combat Alzheimer's at later stages of the disease (mild cognitive impairment and beyond) you need to fight brain inflammation and tau protein tangle accumulation.

The brain inflammation is, in part, mediated by oxidative damage (free radical ions roaming around and taking out proteins, fats, and brain DNA).  This has been known for quite a while, leading to lots of research into vitamin E (a known antioxidant) as an Alzheimer's preventative.  It works great in certain types of mutant mice, but was lousy in experimental trials of humans with MCI or Alzheimer's.  But vitamin E may not be quite specific enough, and lots of alpha-tocopherol (vitamin E) might even deplete our own self-made antioxidant gamma-tocopherol - meaning too much oral vitamin E could be pro-oxidant.  Oops! 

Here's where it gets very interesting for the Kitavans and for certain evolutionary-minded psychiatrists.  The inflammation in Alzheimer's dementia is linked to eicosanoid production (9).   The actual process is dizzyingly complicated, with certain inflammatory markers (such as IL-1beta and complement protein) being pro-plaque and tangle in certain models of the disease, and anti-plaque and tangle at other times.  Seems that complement can lead the immune system to chew up plaques and tangles in an appropriate inflammatory response, whereas in Alzheimer's brains late into the disease, complement reactions are way out of proportion and likely worsen the problem, inviting a bunch of inflammatory fighting forces to the decimated neural battleground.  But, if you recall, the evolutionary medicine theory is that our inflammatory cascade is all out of whack due to the horrible Western dietary imbalance between the inflammatory and anti-inflammatory eicosanoid precursers, omega 6 and omega 3 polyunsaturated acids

Well, if one is too afraid of Unilever and saturated fat to ask people to decrease their omega 6 consumption, one could do something chemically similar by trying to treat Alzheimer's with NSAIDs (naproxen, ibuprofen and the like).   The Anti-inflammatory Prevention Trial (ADAPT) looked at first to be a failure and was halted early over safety concerns.  But, something very interesting happened several years after the naproxen treatment was halted (about two years into the study)(10).  Apparently the treatment group had significant reduction in conversion to Alzheimer's Disease 1.5 years after the naproxen was stopped.  AND measurements of the treatment group's CSF at the same time showed 40% reduction of the tau/amyloid ratio.  That's good, as increasing tau/amyloid ratio is one of the markers of accelerating  cognitive decline in Alzheimer's.   Other studies have shown a reduction in dementia with long term use of ibuprofen (especially in ApoE4 carriers).

Now, since long-term NSAID use can kill your kidneys, cause ulcers and possibly heart attacks and increase gut permeability, it's not a great strategy for a primary population-based treatment of Alzheimer's.  I prefer the Kitavan approach - balance out those omega 3s and omega 6s.  (I'll go into the use of omega 3s as treatment and prevention of Alzheimer's in another post). 

One more thing about those Kitavans - island living may not be particularly stressful.  Chronic expression of the inflammatory cytokine IL-1 can interfere in the regulation of the HPA axis, resulting in the unfortunate elevation of glucocorticoids, like cortisol.  As we've discussed before, long-term excess cortisol is bad for the brain.  Interestingly, many Alzheimer's patients have too much cortisol (called hypercortisolism) that is not fully explained by damage to the hippocampus (11).  In Alzheimer's, the excess cortisol may contribute to insulin resistance and problems with energy regulation in the brain.  And, as we know, energy is everything when it comes to helping out a sick brain.

The boring thing about evolutionary medicine is that we have the same prescription for every problem.  Stop sucking down vast quantities of omega 6.  Eat a diet that won't promote obesity and hyperglycemia.  Get plenty of sleep and lots of play to avoid excess stress.  And who knows, we just might, eventually, prove that government panel wrong, as the Kitavans already have.  So maybe not boring at all, just completely intuitive, relatively simple, and AWESOME.

There is more about Alzheimer's, inflammation, and diet to come.  Much much more!

(picture of neurofibrillary tangle of hyperphosphorylated tau protein from wikipedia)

Copyright Emily Deans, M.D.

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