Myth: Cholesterol Causes Alzheimer's Disease Part I: Debunking the Myth
Published August 1, 2005
Cholesterol is widely blamed for causing Alzheimer's disease. Yet little is known about the relationship between cholesterol and Alzheimer's, and one hypothesis, described below, is that cholesterol protects the brain from Alzheimer's.
It is unsurprising that, when one of the most booming industries is the sale of cholesterol-lowering drugs, just about every disease under the sun would be pinned to cholesterol. The more diseases blamed on cholesterol, the more profits generated by the sale of cholesterol-lowering drugs.
But is it true that cholesterol causes Alzheimer's disease? Or, on the other hand, could you actually harm your brain by reducing its cholesterol content through drugs or a low-fat, low-cholesterol diet? And if cholesterol isn't to blame, what does cause Alzheimer's, and what is the best way to protect ourselves from it?
These questions and more, are all answered below.
Let's All Blame Cholesterol
Headlines blaming cholesterol for Alzheimer's disease abound. A Google search for "cholesterol and the brain" turns up such titles as "Cholesterol central to brain disease," and "Cholesterol bad for brain, too."
One study bragged that by using statins, cholesterol-lowering drugs, medical researchers could reduce the amount of cholesterol in the brains of Alzheimer's patients with normal cholesterol levels by an average of 21.4 percent. Without studying whether this drop in cholesterol resulted in improved memory or other cognitive effects, the study celebrated the ability to reduce normal levels of brain cholesterol based on the dubious notion that cholesterol is "involved" in the formation of amyloid plaques, a hallmark of Alzheimer's disease.
Since the brain, being only 2% of the body's weight, yet containing a full 25% of its cholesterol, relies on cholesterol as so necessary and central to its function, it is not very surprising that cholesterol would be "involved" in any brain disorder.
Yet there is an enormous gap between showing "involvement" of cholesterol and the conclusion that it is a good thing to lower normal brain cholesterol levels by over 20 percent. It is also quite clear that neurons are "involved" in Alzheimer's disease. Yet no one is jumping on the bandwagon to push pharmaceutical drugs that reduce the number of brain cells.
One website recommends adopting a "brain-healthy diet" by "reduc[ing] your intake of foods high in fat and cholesterol." As we will see below, this is anything but a "brain-healthy diet."
Alzheimer's Disease: Some Background
Before we approach the question of whether cholesterol causes (or protects against) Alzheimer's disease, sometimes abbreviated "AD," some background information about this disease is necessary.
Alzheimer's disease was named after Alois Alzheimer, who was a psychiatrist with a specialty in neuropathology, and was the first to show what was going on physically in the brain of someone with what we now call Alzheimer's. In 1907, he presented his findings from the autopsy of his patient, Auguste D., who had been admitted to an asylum for "delerium and frenzied jealousy of her husband."
Alois Alzheimer noted two things about the condition of Auguste's brain, to which he attributed her mental degeneration: "miliary bodies," which we now call "amyloid plaques," and "dense bundles of fibrils," which we now call "neurofibrillary tangles." This was a bold claim at a time when the connection between the physical and the mental was being explored but not yet fully accepted, and in 1910, Alzheimer's mentor, Emil Kraepelin, named the disease after him.1
The amyloid plaques are made up of a peptide (a peptide is a fragment of a protein) called "beta-amyloid," which is formed by the cleavage of amyloid precursor protein (APP) by an enzyme called "gamma-secretase." The tangles, on the other hand, are primarily composed of a protein called "tau," which forms tangles when it is hyper-phosphorylated. The plaques exist on the outside of cells, while the tangles exist on the inside of cells.
The pathology of Alzheimer's disease is very complex, and an attempt is made here to make it simple, while still remaining accurate. The most important pieces of the puzzle to remember at this point are these four:
APP: APP is the precursor of beta-amyloid.
Beta-amyloid: Beta-amyloid forms plaques desposited outside the cells of the brain, which are found in Alzheimer's disease.
Gamma-secretase: Gamma-secretase cleaves APP, yielding beta-amyloid.
Tau: Tau is a protein that, when hyper-phosphorylated, forms the "neurofibrillary tangles" that are found inside cells in the brains of Alzheimer's patients.
The connection between cholesterol and Alzheimer's disease rests on what is called the "amyloid hypothesis," and a somewhat dubious connection between cholesterol and beta-amyloid.
The Amyloid Hypothesis
The amyloid hypothesis of Alzheimer's disease was proposed in 1984 when the structure of beta-amyloid was discovered by Glenner and Wong. The amyloid hypothesis holds that the accumulation of beta-amyloid is the driving force behind amyloid plaques, neurofibrillary tangles, synapse loss (synapses are the connections between neurons), and neuronal cell death. Accumulation is held to occur when the production of beta-amyloid exceeds its clearance from the brain or degradation by enzymes.2
The Cholesterol-Alzheimer's Hypothesis
In this article, I will refer to the idea that high serum or brain cholesterol is a driving force behind Alzheimer's, and that lowering of serum or brain cholesterol through diet or drugs can prevent Alzheimer's, as the "cholesterol-Alzheimer's" hypothesis.
The cholesterol-Alzheimer's hypothesis depends on the amyloid hypothesis, which is controversial in itself. Here is an exceprt from a Science Daily News Release:
"Brain cholesterol is involved in the formation of amyloid plaques, one of the hallmarks of Alzheimer's disease. Amyloid plaques are waxy buildups that harm brain cells.
"'This class of drugs [statins] may be potentially beneficial in the treatment of Alzheimer's disease,' said Dr. Gloria Vega, professor of clinical nutrition and the study's lead author.
"'If we limit cholesterol synthesis in the brain, we may be able to decrease the production of amyloid plaques."
Note that this reasoning relies on two assumptions: 1) high cholesterol levels cause the buildup of amyloid plaques, and 2) it is the buildup of amyloid plaques that drive the neural pathology and cognitive deficits in Alzheimer's disease.
If the cholesterol-Alzheimer's hypothesis is true, it would predict the following:
There should be a clearly defined relationship between serum or brain cholesterol levels and levels of beta-amyloid.
High serum or brain cholesterol should be a risk factor for Alzheimer's disease.
Intervention studies modifying cholesterol levels should not only modify Alzheimer's-related pathology, but should increase or reduce Alzheimer's pathology in direct proportion to the effects on cholesterol, called a "dose-response" relationship. A hypercholesterolemic diet should induce or worsen both physical and cognitive AD-related pathology in proportion to the increase in cholesterol levels, and statins should not only improve the physical and cognitive pathology of Alzheimer's, but they should do so in direct proportion to their effectiveness in lowering brain cholesterol.
Despite the wide-spread blaming of cholesterol for Alzheimer's and the celebration of statins as a possible cure, none of these turn out to be true. The amyloid hypothesis remains highly questionable and unconfirmed; cholesterol's relationship to amyloid levels is inconclusive; high cholesterol is not a true risk factor for Alzheimer's; and, statins do not appear to inhibit amyloid plaques at reasonable doses and can even cause neuronal cell death at high doses.
Problems With the Amyloid Hypothesis
While it is true that the accumulation of amyloid plaques are a universal hallmark of Alzheimer's disease, it does not necessarily follow that they are the primary cause of Alzheimer's disease. There in fact are many other signs of pathology, including the rapid destruction of certain fatty acids and proteins involved in synapse formation. Possibilities outside the conventional amyloid hypothesis include:
beta-amyloid is an irrelevant byproduct of other damage.
beta-amyloid accumulation represents an increased burden on the Alzheimer's brain, but is secondary to more primary causes of degeneration.
beta-amyloid is a byproduct of a neuroprotective mechanism designed to protect against the damage of Alzheimer's.
beta-amyloid is itself involved in a protective mechanism, or is otherwise necessary, but factors entirely separate from it's production cause it to form fibrillary plaques, which may contribute an additional harmful burden.
Scant Evidence in Favor...
According to a review published February, 2005, in Cell, by Rudolph E. Tanzi and Lars Bertram, "Twenty Years of the Alzheimer's Disease Amyloid Hypothesis: A Genetic Perspective," most of the evidence "confirming" the amyloid hypothesis to date has been associations of Alzheimer's disease with genes that are, in turn, associated with a phenotye that includes amyloid plaques.3
Yet such associations are not confirmations of the hypothesis. An association of Alzheimer's with a particular phenotype is merely an association, and does not help us understand causation, any more than an association of fire men with burning buldings "confirms" that fire men are the cause of fires. This is especially true because, as discussed in Part II of this article, the gene mutations associated with AD all have neurodegenerative effects independent of amyloid plaques.
In 2003, a study by Hock et al., attempted to improve cognitive deficits by treating Alzheimer's patients with beta-amyloid immunizations, reasoning that antibodies against beta-amyloid would carry beta-amyloid out of the brain for elimination. Many of the subjects already had endogenous antibodies to beta-amyloid, but the ones whose antibody levels increased significantly over time after immunization performed better on mental examinations than did those whose levels did not significantly increase.
Ten of the thirty test subjects experienced little change in the level of antibodies after immunization, and the rate of increase in the level of these antibodies was never measured in the test subjects prior to immunization. Test subjects who were immunized but did not experience a subsequent rise in antibodies had a worse rate of decline on cognitive tests than than the averages reported in the literature.
The authors of the study regarded it as "the first successful clinical evidence for a central role of beta-amyloid in causing cognitive decline and dementia in AD patients." (My Italics.) Yet the authors themselves concluded that the evidence was decidedly against the antibodies carrying beta-amyloid out of the brain. More importantly, they did not include a control group that was not immunized! Thus, there was no evidence that the immunizations were what caused the antibody levels to rise, and the authors admitted they didn't know the mechanism by which the antibodies improved mental performance.4
In the aforementioned review, Tanzi and Bertram cite a study in which aged rhesus monkeys developed tau phosphorylation and neuronal loss after having pre-assembled beta-amyloid fibrillary plaques injected into their brains. Young rhesus monkeys, on the other hand, did not, and aged monkeys did not respond to soluble beta-amyloid injection. This appears to support a causal role for beta-amyloid fibrillary plaques in the development of other forms of Alezheimer's-related pathology.
Yet, the fact that only pre-formed fibrillary plaques and not soluble beta-amyloid caused pathology are evidence against the amyloid hypothesis's claim that it is accumulation of beta-amyloid that leads to the formation of amyloid plaques and general AD-related pathology. And, as we will see below, there are many more examples where beta-amyloid appears to be independent of other AD-related pathology and not causal.
...And Considerable Evidence Against
While the amyloid hypothesis relies mostly on genetic associations that do not confirm causality, there are many pieces of evidence that contradict the simplistic picture where beta-amyloid deposits are the cause of all other neurodegeneration in Alzheimer's.
One recent study found that changing the amount of DHA, an omega-3 fatty acid abundant in the brain, in the diet of mice that possessed Alzheimer's-related genes, was able to modulate a great deal of the physical pathology and also the cognitive deficits in the mice, independent of the genetically related beta-amyloid accumulation.5
Mice that possess the genes to express amyloid plaques do not exhibit neurofibrillary tangles.6 This suggests that, contrary to the amyloid hypothesis, amyloid plaques are not sufficient to cause the development of neurofibrillary tangles.
A study designed to test whether different forms of beta-amyloid were more or less important to the formation of amyloid plaques found that a particular form consisting of 42 amino acids was necessary for the formation of plaques. Yet it also found "massive" deposition of amyloid plaques in these mice without neuronal loss, tangles, or a general appearance of Alzheimer's.7 This further indicates that, although amyloid plaques are involved in Alzheimer's, they are not the "cause."
One study knocked out the gene for the enzyme presenilin-1 (PS1) in mice. PS1 and PS2 are building-blocks of the gamma-secretase enzyme, which cleaves APP into beta-amyloid, so knocking out PS1 should diminish the accumulation of amyloid plaques. As it turned out, knocking out PS1 diminished amyloid plaques and caused mild impairment of memory.
But with the loss of both PS1 and PS2, the result was "strongly impaired LTP [long-term potentiation, necessary for memory], spatial and contextual memory deficits, and, after some time, massive loss of synapses, dendrites, and neurons. Remarkably, this neurodegeneration was accompanied by increased Tau phosphorylation . . . "8
In this case, decreasing beta-amyloid proved disastrous to the brains of the mice, and resulted in the phosphorylation of tau, which is what is believed to generate the neurofibrillary tangles. PS1 and PS2, which make up the gamma-secretase enzyme, also have many other functions in the nervous system. So, while the study definitely doesn't establish a causal relationship between lack of beta-amyloid and neural degeneration, it certainly calls into question whether beta-amyloid is the driving force behind synapse loss, tau phosphorylation, and the other forms of neurodegeneration that occur in its absence.
Is Beta-Amyloid a Result of Neuro-Protection?
Considerable evidence indicates that beta-amyloid is a byproduct of protective mechanisms. If this is true, it could be that other, more primary, causes of Alzheimer's pathology occur first, and then beta-amyloid accumulation is a result of the brain's self-defense against Alzheimer's-related pathology.
One interesting observation is that Alzheimer's-related pathology occurs in Down's Syndrome patients, but not until middle-age. In this case, it is clear that degeneration occurs before the deposition of amyloid plaques and other outward manifestions of Alzheimer's-related pathology.9
As Bothwell, et al., pointed out in 2000, APP, the precursor to beta-amyloid, is widely preserved across species, which is highly suggestive that it fulfills a function critical to survival.10 As pointed out by Kounnas, et al,11 Mattson showed APP to be neuroprotective,12, Koo showed APP to increase in response to aging,13, and Abe showed APP to increase in response to neuronal injury.14
All these seem to suggest that APP production, and therefore beta-amyloid with it, would increase in response to damage being done to the brain, whether by aging, diet and environment, or genetic defects. This suggests that the beta-amyloid accumulation in Alzheimer's may be a secondary byproduct of a protective response to damage.
The Cholesterol-Alzheimer's Hypothesis Bites the Dust
The cholesterol-Alzheimer's hypothesis relies heavily on the amyloid hypothesis, which remains controversial and has been shown in the preceding section to be seriously questionable. Nevertheless, recent research allows us to evaluate the cholesterol-Alzheimer's hypothesis directly on its own merits, or, rather, its own demerits.
Earlier in the article, we established three criteria for the cholesterol-Alzheimer's hypothesis to meet:
A direct relationship between cholesterol levels and beta-amyloid should be conclusively shown.
High brain or serum cholesterol should be a risk factor for Alzheimer's.
A hypercholesterolemic diet should worsen Alzheimer's in direct proportion to its cholesterol-raising effects, and cholesterol-lowering statins should lower the risk of Alzheimer's in direct proportion to their ability to lower cholesterol.
Are these true? As it turns out, no. Not at all.
The cholesterol-Alzheimer's hypothesis assumes that there is a positive correlation between cholesterol levels and beta-amyloid production. Yet this assumption was based on what reviewer Benjamin Wolozin refered to in Neuron as "highly perturbed systems," in 2004, writing that, "it remains to be seen whether true in vivo alteration of cholesterol alters beta-amyloid."15
Strike one for the cholesterol-Alzheimer's hypothesis.
A February 2005 review in the pages of Molecular Neurobiology analyzed the data available to date and determined cholesterol levels not to be a risk factor for AD. According to the authors:
"Studies were reviewed that have examined cholesterol levels in Alzheimer's pateints and control subjects, including prospective studies, and based on that review, the conclusion is reached that the majority of studies do not support elevated cholesterol levels in serum and brain as a risk factor for Alzheimer's disease."16
Strike two for the cholesterol-Alzheimer's hypothesis.
The authors go on to write that analyzing cholesterol levels into specific sub-categories might be more helpful in identifying risk. This is an important point, because high cholesterol levels are often associated with confounding factors. For example, familial hypercholesterolemia involves a dysfunction of LDL receptors. On the one hand, cholesterol levels in the blood increase because they cannot be received into cells, and on the other, the absence of properly functioning LDL receptors could be causing other problems. Such a dynamic could cause some studies to misidentify a problem as resulting from high cholesterol, rather than a more specific defect of receptors, or even a deficiency of intracellular cholesterol.
In Alzheimer's for example, it has been established that the LDL receptor-related protein, or LRP, is responsible for eliminating beta-amyloid from the brain. But it is also responsible for bringing apolipoprotein-E-associated cholesterol into cells.17 Thus, a deficiency or dysfunction of LRP could be a third factor that results in both increased free brain cholesterol and increased beta-amyloid. Some studies might mistakenly conclude that the high cholesterol level caused the high beta-amyloid level, when the two were actually coincidental.
In addition, it would also be possible to mis-associate the increased free cholesterol with a negative effect in the brain, when it is actually an inability of the cholesterol to exercise its own positive effect in the cells, due to the defect in its receptor.
The cholesterol-Alzheimer's hypothesis has failed our first two criteria. A clear link between cholesterol and beta-amyloid has not been demonstrated. When studies are reviewed together, they do not suggest high cholesterol as a risk factor for AD.
Now for the final nail in the coffin. The third prediction of the cholesterol-Alzheimer's hypothesis is that intervention studies modifying cholesterol should be able to induce or worsen AD through a hypercholesterolemic diet and to ameliorate it through cholesterol-lowering statin drugs. False, and false.
Of the two available studies measuring beta-amyloid changes in response to hypercholesterolemic diets in rodents, one 1998 study found a hypercholesterolemic diet to lower beta-amyloid in proportion to the rise in cholesterol,18 and a 2000 study found the opposite.19
Unfortunately, neither study measured synapse loss, neuronal cell death, neurofibrillary tangles, or any other Alzheimer's-related pathology, which we know can occur independent of beta-amyloid plaques in animals. Nor did either study measure cognitive function of the mice. Thus, neither of these conflicting studies were good measurements of Alzheimer's disease.
Studies with rabbits have been ignored for this article because rabbits are herbivorous and their response to cholesterol is not analogous to that of an omnivore.
There is only one study indexed for Medline that has studied the effect of a hypercholesterolemic diet on any aspect of cognition in animals. This 2004 controlled study found a hypercholesterolemic diet fed to pregnant rats to preserve cognitive functioning in rat pups exposed to anoxia as measured by a linear maze and a Morris water maze.20 A 1995 human study found that feeding eggs as a source of dietary cholesterol was helpful to elderly whose memory was impaired.21
Thus it has never been established that a hypercholesterolemic diet can induce or worsen Alzheimer's disease, and available research suggests that raising cholesterol is generally helpful in improving or preserving cognitive function, not deteriorating it.
What about statins?
Hoglund et al., made three unsuccessful attempts to try to reduce beta-amyloid with statins. In their 2005 report,22 they cite epidemiological studies that showed statin use to result in a lower risk of AD. However, this study did not group the patients by statin dosage, so it was impossible to see if there was a dose-response effect. In addition to this criticism, which the authors note, epidemiological studies are not true "evidence," in that they can be used to generate hypotheses, but never to confirm them.
They go on to cite cell culture and animal studies that showed that cholesterol was correlated with beta-amyloid and that decreasing cholesterol with statins decreased beta-amyloid; however, they rightly criticized these studies as "exceeding clinically relevant doses many times over."
Both clinical and animal studies evaluating the effect of statins on APP are cited as contradictory.
The authors published three studies on the effect of statins on beta-amyloid. In the first study, simvastatin was used on AD patients and found to have no effect on beta-amyloid. The second study used simvastatin or atorvastatin on hypercholesterolemics, and found no effect on beta-amyloid. The third study used simvastatin on AD patients and analyzed their cerebro-spinal fluid for a particular AD-related pattern of beta-amyloids, and found no effect.
Not only was there not an effect on beta-amyloid, but there was a significant reduction of total plasma and LDL cholesterol, and there was a significant reduction in biomarkers for brain cholesterol levels. Thus, we know the dose of statin was high enough to reduce brain cholesterol levels, yet still did not effect beta-amyloid levels.
Strike three. The cholesterol-Alzheimer's hypothesis has struck out.
Cholesterol has not been conclusively tied to beta-amyloid, nor is it a true risk factor for Alzheimer's, and modulating both serum and brain cholesterol through hypercholesterolemic diets and statins does not modulate Alzheimer's-related pathology consistent with the failed cholesterol-Alzheimer's hypothesis.
It is interesting to note that in the report of the study cited above, after failing to control beta-amyloid through statins three times, the authors suggested studying higher dosages of statins, even though they had established their own dosages to be effective in reducing cholesterol.
Yet according to a recent German report, high doses of statins inhibit the growth of dendrites and axons, which form the connections between neurons, and induce neuronal apoptosis, which is a fancy way of saying they make brain cells commit suicide.23
Since cholesterol is vital to the brain and is the limiting factor in the formation of synapses, it is unsurprising that drugs lowering brain cholesterol could damage neurons.
In fact, Iwo J. Bohr has recently presented the hypothesis that cholesterol is protective against Alzheimer's disease!
Cholesterol Is the Brain's Best Friend
That cholesterol plays a central role in the development and maintenance of the brain and nervous system is reflected by the fact that the human brain makes up only two percent of the body's weight, yet contains nearly 25 percent of its cholesterol.24
Over the last five years, new research has been elucidating the role of cholesterol in the brain and highlighting its vital importance. For example, in 1997 it was discovered that an unknown factor secreted by glial cells, which grow alongside neurons, was the limiting factor allowing the growth of synapses, which are the connections between neurons.
In 2001, this unknown "glial factor" was identified as cholesterol. In the absence of the glial secretion, the neurons formed few and inefficient synapses. When the glial secretion was supplied intact but deprived of cholesterol, it was ineffective. When neurons deprived of this glial secretion were exposed to a solution of cholesterol, synapse formation increased by twelve times. Synapses formed in the presence of the cholesterol-containing glial secretion were highly efficient and highly functioning.25
Cholesterol has also been discovered to play an important role in forming what are called lipid rafts, areas in the plasma membrane of cells that anchor certain proteins important to cell signaling.26
A 2004 study found that several of the proteins anchored in these lipid rafts are responsible for stimulating and guiding the growth of nerve axons. Depriving the membrane of cholesterol selectively inhibited the effect of attractive signaling proteins, which destroyed the axon's ability to grow in the proper direction.27
Thus, cholesterol is the limiting factor in the ability to form synapses and for nerve growth per se, and is also essential to the regulation of that growth, so that synapses form properly and in the right places.
Is Cholesterol Protective Against Alzheimer's Disease?
On June 10, 2005, Iwo J. Bohr's new hypothesis was released from peer review and published in Lipids in Health and Disease, hypothesizing that cholesterol is a protective factor in Alzheimer's disease.28
As background, Borh cites a hypercholesterolemic diet as protective of cognitive function in rats and a high cholesterol level's association in humans with lower mortality and a better outcome following a first stroke. He also points out that Alzheimer's patients have lower levels of cholesterol in serum, brain membranes, and in lipid rafts, and that Alzheimer's has been related to the downregulation of a gene involved in cholesterol synthesis.
Bohr's hypothesis is that APP plays a role in bringing in apolipoproteinE-enriched cholesterol into cells, which is a protective response to neuronal damage. Since AD pathology targets a type of nervous system receptor called "cholinergic receptors," and these receptors are cholesterol-dependent, as aging or other forms of stress damage the cholinergic receptors, the need for cholesterol in the brain is increased.
According to Bohr's hypothesis, a higher demand for cholesterol will cause APP metabolism to increase, and would result in greater beta-amyloid accumulation. The increased demand for cholesterol could be generated both by aging or other oxidative damage, or due to a deficiency in the ability to bring it into cells. One specific form of the gene for apolipoprotein E referred to as the epsilon-4 allele, for example, makes the brain less efficient at bringing cholesterol into its cells.
Neurobiology of Lipids has informed me of several articles in which a similar hypothesis was presented earlier. These will be reviewed and this article will be changed to properly credit Dr. Koudinov. An update will also appear in our free newsletter.
For a list of review articles on Alzheimer's and cholesterol please follow this NIH PubMed link.
You may also access the journal Neurobiology of Lipids, a journal on every aspect of lipids, neuroscience, and their application to health care, by clicking on its logo, below:
Finally, for more information on Dr. Koudinov's contribution, click here.
Is Bohr's hypothesis correct? More testing is needed. But one thing is clear: far from it being established that cholesterol causes Alzheimer's, the precise opposite may well just turn out to be true. If it is, depriving the brain of cholesterol through a low-fat, low-cholesterol diet or cholesterol-lowering drugs, could have the potential to make Alzheimer's disease worse.
A Radical High-Fat Diet May Protect Against Alzheimer's
While many authors, contradicting all available scientific evidence, will advocate a "brain-healthy diet" as one that is low in fat and cholesterol, it is ironic that the one diet that has a substantial body of evidence showing its benefits to patients of neurological diseases is the low-fat diet's antithesis: the ketogenic diet.
In a 2003 review in Nutrition Reviews, Dr. Theodore B VanItallie and Thomas H Nufert outlined the history of the ketogenic diet, the evidence supporting its effectiveness, and the case for testing its possible therapeutic value for Parkinson's disease and Alzheimer's disease.29
The ketogenic diet was first reported as effective in treating epilepsy in 1924, after it had been proposed three years earlier by Woodyat and Wilder of the famous Mayo Clinic. The ketogenic diet is, gram for gram, 80 percent fat, which results in a diet that supplies 90 percent of its calories as fat, five percent as carbohydrate, and five percent as protein.
The ketogenic diet causes a large increase in the circulation of ketones. Certain ketones protect neurons in the brain from excitotoxic effects, and they supply a more efficient form of energy to the brain than glucose, especially in certain neurological disorders, such as Alzheimer's, where glucose metabolism is impaired in the brain and localized insulin resistance has taken hold.
Among eplileptic patients who adhere to the ketogenic diet, 40 percent experience greater than 90 percent reduction in seizures, and an additional 40 percent experience 50 to 90 percent reduction!
The ketogenic diet is difficult for patients to adhere to, but its therapeutic value is undeniable. It has been proven to be clinically effective, and research on the benefits of ketones to the brain has accumulated in the near-century since its first clinical use.
Conversely, there is no evidence to support any such dramatic clinical reversal of a neurological disease with a low-fat diet or low-cholesterol diet.
VanItallie and Nufert make the case that a ketogenic diet should be tried for therapeutic effectiveness in Alzheimer's disease: Alzheimer's has been linked to insulin resistance in the brain, and a ketogenic diet can restore metabolic efficiency in such cases. Most strikingly, the addition of beta-hydroxybutarate, a ketone, to cell cultures protects them from harmful effects of beta-amyloid fragments.
Once again, not only are the recommendations of the cholesterol-Alzheimer's hypothesis not supported by science, but sound scientific research appears to support just the opposite: an extremely high-fat diet may be therapeutic in Alzheimer's disease.
Cholesterol, the Unsung Hero
While it is widely popular (and profitable) to blame Alzheimer's disease on cholesterol, and thereby advocate a low-fat, low-cholesterol diet to prevent Alzheimer's, and the use of statin drugs to prevent or treat Alzheimer's, the connection has been exposed as nothing more than myth.
The cholesterol-Alzheimer's hypothesis claims that high cholesterol causes the accumulation of beta-amyloid, and that the accumulation of beta-amyloid is the driving force behind all Alzheimer's-related pathology.
Yet cholesterol has not been conclusively linked to beta-amyloid, and some studies suggest an inverse correlation between the two. That beta-amyloid accumulation is the driving force behind Alzheimer's-related pathology has yet to be demonstrated, and is called into question by animal experiments that show many AD-related pathologies to take place independent of beta-amyloid.
In the midst of the anti-cholesterol hysteria, research continues to show that cholesterol is the most vital and important substance in our brains. It is cholesterol that allows our neurons to form synapses so that we can learn, remember, and think. Cholesterol appears to be important to the brain's reaction to nerve damage, and its most important role in Alzheimer's disease may be as a protective factor.
Cholesterol truly is the unsung hero of the brain.
Just What does Cause Alzheimer's?
So if cholesterol isn't the culprit, what is? Are there dietary measures we can take to protect ourselves? Are there lifestyle choices we can make to protect ourselves?
Yes. While cholesterol is not one of them, there are many factors in Alzheimer's, some of which are controllable, some of which are not, that have been demonstrated with varying degrees of conclusiveness by real science to play a central role.
End Notes
1. Tanzi, Rudolph E., and Lars Bertram, "Twenty Years of the Alzheimer's Disease Amyloid Hypothesis: A Genetic Perspective," (Review), Cell, Vol. 120, 545-555, February 25, 2005.
2. ibid
3. ibid
4. Hock, et al., "Antibodies Against beta-Amyloid Slow Cognitive Decline in Alzheimer's Disease," Neuron, Vol. 38, 547-554, May 22, 2003.
5. Calon, et al., "Docosohexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model," Neuron, Vol. 43, 633-645, Sept. 2, 2004.
6. ibid
7. McGowan, et al., "A-beta42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice," Neuron, Vol. 47, 191-199, July 21, 2005.
8. Marjaux, et al., "Presenilins in Memory, Alzheimer's Disease, and Therapy," Neuron, Vol. 42, 189-192, April 22, 2004.
9. Tanzi and Bertram, 2005.
10. Bothwell, et al., "Alzheimer's Disease: Neurodevelopment Converges with Neurodegeneration," (Minireview), Cell, Vol. 102, 271-273, 2000.
11. Kounnas et al., "LDL Receptor-Related Protein, a Multifunctional ApoE Receptor, Binds Secreted beta-Amyloid Precursor and Mediates Its Degradation," Cell, Vol. 82, 331-340, 1995.
12. Mattson, et al., "Evidence for excito-protective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein," Neuron, 10, 243-254, 1993.
13. Koo et al., "Differential expression of amyloid precursor protein mRNAs in cases of Alzheimer's disease and in aged nonhuman primates," Neuron, 2, 97-104.
14. Abe, et al., "Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischemia in rat cerebral cortex," Neurosci. Lett., 125, 172-174, 1991.
15. Wolozin, Benjamin, "Cholesterol and the Biology of Alzheimer's Disease," (Minireview) Neuron, vol. 41, 7-10, Jan 8, 2004.
16. Wood, et al., "Is Hypercholesterolemia a Risk Factor for Alzheimer's Disease?" Molecular Neurobiology,, (Review) February 2005, vol. 31, 1-3, 185-192.
17. Kounnas, 1995.
18. Howland et al., "Modulation of Secreted beta-Amyloid Precursor Protein and Amyloid beta-Peptide in Brain by Cholesterol," J Biol Chem, Vol. 273, Issue 26, 16576-16582, June 26, 1998.
29. Refolo et al., "Hypercholesterolemia Accelerates the Alzheimer's Amyloid Pathology in a Transgenic Mouse Model," Neurobiology of Disease, Vol 7, Issue 4, August 2000, 321-331.
20. Bohr, I., "Hypercholesterolemic diet applied to rat dams protects their offspring against cognitive deficits. Simulated neonatal anoxia model." i> Physiol Behav. 2004, Sep 30; 82(4):703-11.
21. Singer, 1995, as cited in Enig, Know Your Fats: The Complete Primer for Understanding the Nutrition of Fats, Oils, and Cholesterol Silver Spring: Bethseda, 2000, p. 57.
22. Hoglund et al., "Statin treatment and a disease-specific pattern of beta-amyloid peptides in Alzheimer's disease," Exp Brain Res (2005) 164: 205-214.
23. Bosel and Endres, "Direct neuronal effects of statins," Nervenartz 2005 Jul 19 [Epub ahead of print.]
24. Dietschy JM, Turley SD, "Cholesterol metabolism in the brain," Curr Opin Lipidol, 2001, 12: 105-112.
25. Mauch et al., "CNS Synaptogenesis Promoted by Glia-Derived Cholesterol," Science, Vol. 294, 1354-1357.
26. Alberts, et al., Molecular Biology of the Cell: Fourth Edition," New York: Garland Science, 2002, 589-590.
27. Guirland, et al., "Lipid Rafts Mediate Chemotropic Guidance of Nerve Growth Cones," Neuron, Vol. 42, 51-62, April 8, 2004.
28. Borh, Iwo J., "Does cholesterol act as a protector of cholinergic projections in Alzheimer's disease?" Lipids in Health and Disease, 2005, 4:13.
29. VanItallie and Nufert, “Ketones: Metabolism’s Ugly Duckling,” (Review) Nutrition Reviews, Vol. 61, No. 10, October 2003: 327-341.