Striking Alzheimer's before it strikes

Those following the news on trials of drugs against Alzheimer's disease must be familiar with the depressing outlook from the front lines. There was a string of failures reported in the last few years for therapies intended to disrupt the beta amyloid protein in AD. The failures have sent researchers back to the drawing board and the beta amyloid hypothesis itself has been strongly questioned. Amyloid is almost certainly involved in some big way with the disease, but its exact role as a causative agent has been under scrutiny for a while now.

Several factors could be responsible for the failure of these trials, but one factor in particular was bandied about as an obvious one; perhaps the intervention came too late to help the patients. We now know that diseases like AD and cancer often kick in quite early when they are beyond the detection limit of current diagnostic techniques. Perhaps, the thinking goes, we might stand a chance of beating the disease if we intervene early enough.

This thinking is completely sound, except for the problem that there is even now no definitive test to detect AD at very early stages. Fortunately for scientists - and quite certainly unfortunately for those unlucky enough to draw from this lottery - there are certain populations which are genetically predisposed to the disease. Members of these families typically get the disease in their 40s and by the 50s they are completely debilitated by it. The most prominent of these groups is an unfortunate family in Colombia, and the New York Times reported on them in 2010.

Now the Times reports on a drug trial designed to test the early intervention hypothesis in this clan. The drug in question is an antibody targeted against amyloid called crenezumab. The antibody was developed by Genentech and the preventative study is being jointly funded by the company, the NIH and a private foundation. Naturally it's going to be a long-drawn project; suspected patients are going to be started on the treatment when they are as young as 30, and their progress will be monitored meticulously over the next several years through both diagnostic mental tests and non-invasive techniques like PET scans.

This is a very hopeful and well thought-out experiment, and just like Derek who blogged about this today, I wish both the patients and the researchers the very best. Sadly, the history of the AD trials cited above does not fill me with too much hope. The amyloid hypothesis has constantly been under attack for the last decade or so. The most significant discovery in this regard was the finding that small oligomers of the protein rather than the full misfolded form might be the real culprit; but crenezumab seems to function by attacking the full form.

More intriguing and disturbing are the potential consequences for the normal health of the patients. Amyloid is definitely part of the normal functioning of the human body but nobody knows its exact function yet. However, it seems clear that the misfolded and normal soluble form of the protein are in some kind of equilibrium with each other. More interestingly, recent reports have implicated amyloid as an antibacterial agent. There's also some longstanding studies that suggest that amyloid forms free radicals which are usually toxic, but which may also help kill bacteria. I myself had speculated on amyloid's possible evolutionary role as a defense mechanism.

All this makes me skeptical about disturbing the normal vs misfolded amyloid equilibrium as a long-term strategy; the process may well be a crucial one, and killing the messenger might kill the message. Everyone wants this trial to succeed but we probably shouldn't be surprised if something disappointing shows up. One thing's for sure; this stuff will generate a lot of data, and that's what science is about.
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Will quantum physics help us cure Alzheimer's disease?

There's an interesting bit of writing out in the journal ChemMedChem by Jean-Louis Kraus, a medicinal chemist in France who has worked on drug discovery for Alzheimer's disease. The article is essentially a summary of Kraus's pessimistic outlook towards current therapies and approaches addressing Alzheimer's disease. Kraus has worked for a long time in medicinal chemistry and his words reflect experience and not just opinion. The article starts off with some well-founded skepticism but ends up sounding...let's say a little questionable.

For the most part I agree with Kraus that Alzheimer's research in the last decade has seen one disappointment after another and that we are still largely groping in the dark. He refers to the fact that all the concerted research into the disease and the billions of dollars in funding have resulted in only a handful of drugs and a handful of protein targets. None of the drugs even partially repair the damage and none of the proteins have been shown to be decisive as targets for treatment. Beta-secretase, gamma-secretase, the NMDA receptor, acetylcholine esterase; all of these have seen their day in the sun, followed by a disappointing set of results usurping them from front stage. That doesn't mean that none of them are important, it's just that targeting them with therapies seems to have no direct causal connection with treating the disease.

But what is even more disappointing is that the basic hypothesis driving the field - the amyloid hypothesis - has now been seriously questioned. A series of high-profile clinical trial failures have sent researchers scurrying back to their benches and while amyloid almost certainly has an important connection with the disease, it's now not clear at all whether actually targeting the infamous protein aggregates will bring any benefits. What seemed like a promising and rather direct direction of research has devolved into a scientific mess that will need at least a few years to be sorted out. As far as Alzheimer's disease goes, we are still fighting with sticks and stones.

As Kraus says, much of this failure eventually is a failure to understand the basic biology of the disease, which in turn entails a failure to understand the brain on a more general level, including mechanisms of memory generation and storage. Even now, much of drug discovery fails because of ignorance of the detailed biology of the disease and its perturbation by small molecules. What is regarded as a sound mechanistic hypothesis is often thwarted by the complex realities of signal transduction. With Alzheimer's disease we seem to have been biting off more than we could chew, and we need to keep untangling the complex interplay of amyloid, the protein tau, the secretases and a multitude of other biochemical components before we can truly start developing therapies. Thus it's inevitable and essential that in addition to chemists and biologists, we will need crucial input from neuroscientists to target the disease.

But will we also need quantum physicists? Kraus's thoughts on the relevance of subatomic science to AD left me slightly nonplussed. He says that:

The theories behind black holes generally suggest that subatomic particles (electrons, protons, neutrons) are themselves black holes, in which time expands in the opposite direction of our proper (perceived) time. Huge amounts of information could be stored by the spin number of photons present in these particle black holes. Could it be possible that the organization of brain matter, in terms of the properties of subatomic particles (quantum mechanics), confers on brain matter the capacities of memory and cognition, and that these phenomena are not encountered in other types of matter structure in the human body?

Come again? I was not familiar with electrons, protons and neutrons being black holes. But even if they are, I fail to see their direct relevance to understanding memory and cognition. Sure, it's a trivial fact that it's a very specific organization of subatomic particles that leads to a brain rather than to a liver or a chair. But the real action all takes place at the level of aggregates of these particles which we call molecules. I get the feeing that Kraus is indulging in a classic reductionist fallacy here. While subatomic particles do constitute the brain, understanding the brain can only come at a higher level, that of rather old-fashioned physics and chemistry involving ionic currents and neurotransmitters.

But Kraus finds a valuable place for quantum physicists in the war on neurodegenerative disorders:

To me it has become mandatory to create an AD scientific community that includes not only medicinal chemists, pharmacologists, biologists, and medical doctors, but also quantum physicists, in order to understand how aging alters the intimate structure of brain matter, where memory and cognition are located, with the hope of finding new AD treatment research orientations.

To me this sounds suspiciously like Roger Penrose's argument in his rather startling book "Shadows of the Mind" in which he postulated a relationship between wavefunction superposition in quantum mechanics and the growth and shrinkage of microtubules as significantly contributing to consciousness. Even a cursory look at that argument raised serious doubts about the relevance of quantum behavior in microtubules and more formal analysis seemed to confirm these doubts. I am not saying that physicists won't be a valuable asset on a drug discovery team, it's just that they are probably not going to use the tools of quantum gravity to map out cognitive pathways anytime soon.

Somewhat ironically, Kraus ends his piece by extolling the role of a systems biology approach in addressing a problem as complex as Alzheimer's disease. With this I wholeheartedly agree, but systems biology is the opposite of reductionism, where new emergent phenomena provide causal explanations that cannot be reduced to the laws underlying their substrates. We do need a suite of analytical tools operating at various hierarchical levels to address the issue, but given enough time and smart people, we should be able to do the job using standard chemistry and biology, albeit at a more sophisticated level. No fancy biophoton entanglement may be necessary.

Kraus, J. (2011). Why as a Medicinal Chemist I Am Not Optimistic about the Possibility of Finding, in a Reasonable Timeframe, Small-Molecule Drugs Capable of Curing the Evolution of Alzheimer’s Disease ChemMedChem DOI: 10.1002/cmdc.201100431

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The barrier to amyloid formation is kinetic, not thermodynamic

One of the questions I have pondered in the past is why the functional form of a protein should correspond to its most thermodynamically stable structure. Although this assumption is built into almost all experimental and theoretical studies of protein folding, it is not at all obvious since one may imagine other forms which could have improved stability. For instance, two protein forms may differ in the presence of a hydrogen bond or two. Based on the location and connectivity of these bonds, sometimes this slight rearrangement can cause a radical change in function, but there's no good reason why it should in the general case.

The answer however is most obvious in case of amyloid, that endlessly intriguing protein form that is implicated in so many devastating neurological disorders. Amyloid is a very stable state is often highly resistant to temperature, pH and high salt conditions. It's fair to ask how stable or unstable it is with respect to functional, soluble forms of the same protein.

To answer this question, a team led by Christopher Dobson who is a world expert on amyloid performed a series of thermodynamic measurements on a diverse group of proteins in which they measured the free energy differences between the soluble and the amyloid state. The proteins included everything from the Aß protein found in Alzheimer's disease to human lysozyme and insulin. The finding was that the free energy differences (ranging from about 3 kcal/mol to 6 kcal/mol) are not terribly dependent on the exact sequence, an observation which would be consistent with the striking recently uncovered fact that amyloid formation can be induced in almost any protein independent of its sequence. In fact the free energy difference seemed to depend more on the length and seemed to be optimal for a length of 100 residues for which the amyloid form was most stable. The difference also sharply tipped away from amyloid for increasing lengths.

This observation seems to suggest that one consequence of evolving larger proteins might be steer them away from the amyloid state and is consistent with the fact that almost all amyloid proteins have relatively short lengths (for instance, the Alzheimer's disease amyloid protein Aß has a length of roughly 40 residues). The propensity toward amyloid formation also depended on the concentration and the authors derived an limiting concentration beyond which amyloid formation would be rapid. This is again not surprising since the concentration-dependence of the process has also been demonstrated.

The real surprise came when they compared these limiting concentrations of the protein to the corresponding physiological concentrations of the same proteins in plasma. Remarkably, they found that in almost every case the physiological concentration was higher than that required to achieve amyloid formation. Thus the observations clearly indicate that for many key proteins, the amyloid state is thermodynamically more stable than the native, functional state. To put it bluntly, many nicely folded and soluble proteins are actually metastable. Now, since native proteins don't constantly form amyloid and kill us all, it's clear that the barrier to amyloid formation must be kinetic. Intriguingly, the authors speculate that these barriers can be overcome when organisms are exposed to stress, mutations or aging.

This is a pretty intriguing study and seems to underscore the belief that at least for some proteins, the folded functional state is not the most stable. However in light of what we know about evolution, this should not be too surprising. Stability is just one of many factors to be optimized during natural selection and there is no reason to assume that evolution would always act to maximize this parameter at the cost of all others. It's worth always keeping in mind that evolution cannot afford to aim for the ideal but instead has to make do with what it has.

The other question in my mind is why in spite of these barriers existing in case of so many proteins like lysozyme, insulin etc. are they regularly overcome only in the case of Aß (1-42) and a select few others. Based on the speculation in the paper, this could be because these proteins are exposed to particularly harsh conditions that force them to climb past the kinetic barrier and settle into the amyloid valley of thermodynamic comfort and physiological woe.

Among many such conditions could very well be bacterial infections. A few years back I advanced a hypothesis about amyloid formation being a defense against viral and bacterial infection mediated through the production of free radicals. A kinetic barrier-surpassing mechanism of the kind speculated here might well be what allows these proteins to achieve the transition, killing the bacteria but ironically harming their owner in the process. In the context of the present study, I think there continue to be a lot of opportunities to investigate the possible infection-induced conversion of normal proteins to their amyloid form.

Hopefully someone will do the experiment.

Baldwin, A., Knowles, T., Tartaglia, G., Fitzpatrick, A., Devlin, G., Shammas, S., Waudby, C., Mossuto, M., Meehan, S., Gras, S., Christodoulou, J., Anthony-Cahill, S., Barker, P., Vendruscolo, M., & Dobson, C. (2011). Metastability of Native Proteins and the Phenomenon of Amyloid Formation Journal of the American Chemical Society DOI: 10.1021/ja2017703

Probing amyloid, one oligomer at a time

One of the more important paradigm shifts in our understanding of the Alzheimer’s disease-causing amyloid protein in the last few years has been the recognition of differences between the well known polymer aggregates of amyloid and their smaller, soluble oligomer counterparts. For a long time it was believed that the fully formed 40-42 amino acid protein aggregate found in autopsies was the causative agent in AD, or at least the most toxic one. This understanding has radically changed in the last few years, partly through elegant work done in identifying oligomers and partly through the unfortunate results of clinical trials targeting amyloid. The new understanding is that it’s not the fully formed aggregates but the smaller oligomers that are the real toxic species.

Identifying these different monomers, dimers, trimers and tetramers is a valuable goal. But until now their recognition has mainly depended on raising specific antibodies against them, a tedious and expensive process. Small molecule probes that specifically identify each oligomer have been missing. In a recent JACS communication, a team from the University of Michigan uses a simple but clever technique to develop such probes and makes a promising step in this direction.

The probes are based on the idea that the best antidote against a poison is another poison. In this case the poison is the specific sequence of amino acids that makes up amyloid. In particular, a sequence of five amino acids- KLVFF- has been found to be sufficient for aggregation and toxicity. The aggregates form by the stacking of beta sheets principally driven by hydrophobic interaction between the FF residues; each pair thus serves as a growth site for addition of further such residues. The insight then is that if one could construct a mimic of the sequence, this mimic would basically act as a competitive inhibitor and bind to the normal sequence, inhibiting further growth. In this case the strategy was to use KLVFF segments themselves which would sort of wrap around newly formed oligomers of different constitution and sequester them from further self-assembly. So the team essentially constructed two KLVFF segments joined by a linker. The linker would also serve the purpose of providing an entropic advantage to the two segments so that they would not be at an energetic disadvantage during binding. The important question was how long the linker should be.

To decide on the length of the linker the team made some clever use of molecular dynamics simulations. Since you can estimate the approximate thickness of every oligomer, you can estimate the linker length that would be required to keep two KLVFF segments at the same distance as the thickness of the oligomer. For instance, the distances between the segments needed to wrap around the oligomers were 14-15 A for the dimer, 19-20 A for the trimer and 24-25 A for the tetramer.



But the linker should also keep the segments stable at that distance. To probe this the team used MD simulations. The MD simulations revealed the length of the linker required to keep the two segments separated at the specific distances by indicating how much time the assembly spent at those distances.

To test these results, the team then generated mixtures of different kinds of KLVFF oligomers and then added each probe to the solution. A streptavidin moiety was attached to every probe. Silver staining revealed that each probe was specifically binding to an oligomer of a certain type dictated by the compatibility of the intraprobe distance and oligomer thickness. Trimers and tetramers could be clearly identified but there was more ambiguity in case of dimers, presumably because of their less ordered structure.

Most interestingly, the team then added the probes to cerebrospinal fluid (CSF). Since amyloid is part of normal physiology, it is present in CSF. Gratifyingly they found that the probes could very clearly label trimers and tetramers against a background of several other proteins and intermediates in CSF. This experiment notably demonstrates that the method can selectively detect amyloid oligomers in complex mixtures.

I think that this work is valuable and paves the way toward the development of similar small-molecule based probes for identifying the key intermediates in amyloid formation. It could also be very useful in exploring amyloid formation in normal physiology and in exploring the stages of protein self-assembly in diverse amyloid-based diseases.

Reinke, A., Ung, P., Quintero, J., Carlson, H., & Gestwicki, J. (2010). Chemical Probes That Selectively Recognize the Earliest Aβ Oligomers in Complex Mixtures Journal of the American Chemical Society DOI: 10.1021/ja106291e

Miles to go before...

A New York Times article describes a study conducted by the NIH that basically asked scientists to simply sift through the massive evidence of the past twenty years to answer one question; what factors can cause or prevent Alzheimer's disease? The answer is unsurprisingly depressing- there is basically no proven therapy, personal habit, dietary supplement or mental task that correlates with the prevention of AD. AD is still as much a disease without a cure or preventative remedy as it ever was. We have almost as much work to do as Alois Alzheimer would have in 1908.

The bad news about AD has just kept on coming in over the last few years. Part of the reason is the very disappointing verdict on the role of beta-amyloid, reached after dozens of clinical trials which targeted the clump of protein in AD brains and failed to reverse the debilitating effects of the disease. Along with these studies, there has been a panoply of articles suggesting everything from crossword puzzle solving to Gingko biloba extracts that could possibly prevent the disease.

But as the NYT article reports, most of these recommendations are based on faulty 'studies' which are typically called "observational" studies. These studies are essentially accounts of observations made after someone has started on a measure that's assumed to be preventative. In addition, most of these observations are self-reported. Thus, evidence from such observations is spotty at best and is a far cry from the double-blind controlled clinical trials required to establish efficacy. After sifting through the evidence, the NIH study group concluded that they were sure only about one measure- Gingko biloba. And here the verdict was that Gingko biloba does not prevent AD. Apart from this, most other factors touted as preventive measures- including cognitive stimulation, vitamin E and antioxidants- could not be correlated with decreased incidence of AD with any degree of certainty. There's just no good evidence.

Part of the problem is simply the amount of time patients enrolled in trials would have to be observed in order to draw any conclusion about prevention. AD typically emerges around age 50, but its effects become apparent only in the late 60s and early 70s. A true clinical trial to study prevention would probably have to start during the young years and subjects would have to be followed for at least two to three decades, an expensive and complicated endeavor.

Yet the reports cited in the NYT should not be as depressing as they appear. For one thing, many people now think that the real reason none of the therapies for AD are working is simply because they are administered too late. Two new promising studies based on PET scans and spinal taps could make it easier to detect AD earlier and start treatment immediately. Plus, it's precisely the fragmented nature of the reported observations that provides opportunity for studying them further. Also, as depressing as the amyloid-targeting trials were, at least they provide good evidence of something that does not seem to be working. In science, the misses are almost as important as the hits. Finally, it's not like long-term studies cannot be attempted; the famous Framingham study followed the inhabitants of a small Massachusetts town not just over years but over generations to establish the connection between high cholesterol and heart disease. Perhaps a Framingham-style study for Alzheimer's is due.

Until these deep questions are resolved though, AD patients and their families will keep on living their private version of hell and will keep on trying to stave off the terrible malady by trying anything that remotely seems to work. The least we can all do is keep on searching.

Open-sourcing Alzheimer's diagnosis

In the middle of all that disappointing news about failed treatments targeting beta-amyloid, here's some silver lining. A lot of people think that the real reason all these drugs are not fighting AD is not because they are ineffective per se but because they are administered too late, long after the disease has manifested itself. Thus the logical step toward making these therapies more effective would be in detecting AD earlier. In the last few months, a slew of articles has detailed several techniques for diagnosing AD early which look promising, from better brain imaging to spinal taps. An article in today's New York Times looks at the integrated effort that has spawned these developments. It turns out that the effort has come about from several government agencies, universities, non-profit organizations and imaging and pharmaceutical companies collaborating to find early biomarkers for AD. The joint initiative has pooled together several million dollars from each contributor. As everyone wisely realized, AD is much too complex to be tackled by single research entities (what disease isn't?). As one participant said:

"We all realized that we would never get biomarkers unless all of us parked our egos and intellectual-property noses outside the door and agreed that all of our data would be public immediately.”

"Parking their egos" outside would be necessary for the diverse and large studies required to gain insight into true AD biomarkers.

“The problem in the field was that you had many different scientists in many different universities doing their own research with their own patients and with their own methods,” said Dr. Michael W. Weiner of the San Francisco Department of Veterans Affairs, who directs ADNI. “Different people using different methods on different subjects in different places were getting different results, which is not surprising. What was needed was to get everyone together and to get a common data set.”
But that would require a huge effort. No company could do it alone, and neither could individual researchers. The project would require 800 subjects, some with normal memories, some with memory impairment, some with Alzheimer’s, who would be tested for possible biomarkers and followed for years to see whether these markers signaled the disease’s progression.

The problem is of course is that it can be tricky as hell to distinguish true biomarkers from spurious ones (the old problem of distinguishing correlation from causation). It would take some time to zero in on those biomarkers that truly signal the onset of the disease. But this bit of news is gladdening for two reasons; firstly because it indicates that people are perhaps moving away from the obsession with targeting amyloid (which nonetheless continues to be a fascinating entity), and more importantly because it indicates that there are still people willing to park their egos outside the door and publicly collaborate to address a very complex medical challenge. Hopefully this endeavor should provide inspiration for tackling other diseases.

The beta-amyloid hyp(e)othesis; the saga continues

As Churchill would have said, beta-amyloid is a riddle, wrapped in a mystery, inside an enigma. For years now, the "amyloid hypothesis" has been widely-accepted as somehow being importantly responsible for Alzheimer's disease. A few years back researchers were cheerfully confident that amyloid was to AD what artherosclerotic plagues were to heart disease. Rudolph Tanzi, a Harvard neurologist who is a leading authority on the disease and identified the first AD gene, had this to say in an interview in 2000:

Q. How close are we to an effective treatment for Alzheimer's disease?
A. I wouldn't be surprised if five years from now we have a pretty effective drug that can slow the disease down enough so that it will be preventable in those at risk, and significantly slow down the deterioration of people who already have it.

Q. Why do you have such optimism?

A. Because, in 15 years, we've gone from knowing little about what causes this disease to having a pretty concrete idea of which biological pathways and body proteins are involved.

If you compare Alzheimer's to heart disease where cholesterol levels must be lowered, we now have our own cholesterol equivalent, which we call the beta-amyloid. The name of the game in Alzheimer's therapy is lowering the accumulation of beta-amyloid in the brain.

It's ten years later and we are no closer to finding an AD drug. Tanzi's hope was not unwarranted given what we knew about amyloid then. But as the amyloid hypothesis matured, so did our understanding of it. First we discovered that it's not the amyloid aggregates themselves but soluble oligomers that are probably responsible for neuronal toxicity. Now it has been proposed that amyloid could have a protective antimicrobial role (I myself had an evolutionary speculation on this) in which case targeting it could even be dangerous. The fact remains that there is no proof that amyloid causes AD. It certainly seems to be related in an important way and many revealing details about it have been uncovered in the last decade, but the proof of principle has been on an increasingly slippery slope and if anything the picture gets murkier and more fascinating.

An article in the latest issue of C & EN basically says that we are targeting beta-amyloid because at least for now we cannot think of anything better to do. It's true that currently, our best bet at treating AD lies in interfering with amyloid formation. But since amyloid formation has never been shown to be causative for AD, treatments targeted at it are always going to be something of a shot in the dark. The advantage of targeting amyloid formation though, as the article says, is that there are lots of points in the mechanism where one can potentially interfere. Two key enzymes responsible for formation of amyloid are beta and gamma-secretase, which clip the amyloid precursor peptide into apparently toxic fragments. Scores of articles are published every year about new chemical agents targeting these two enzymes, and yet the jungle is thicker than we think.

Gamma-secretase is actually a multiprotein complex whose structure is not known, so finding molecules that inhibit it is like finding a black cat in a dark room. More importantly, it's also involved in a second pathway called the Notch pathway which is critical in cell-signaling. Thus blocking it may lead to one of the classic problems in drug discovery whereby eliminating a harmful function also eliminates a useful one, often fatally. Beta-secretase is much more well-studied and its crystal structure has been solved, but it poses a classic structure-based design conundrum; the enzyme's active pocket is flexible and expansive and can bind many ligands in different subpockets. Thus, developing drugs that block this moving target is admittedly challenging. Throw in the requirements for safety and an ability to cross the blood-brain barrier (BBB), and we have a pickle on our hands that's almost as dense as amyloid plaques.

But the much more serious issue is whether any of these strategies will work at all. If amyloid formation turns out to be a side-show in AD progression, then all these strategies might ultimately come to naught. Unfortunately the data so far is not promising. The last few years have seen a disappointing string of late-stage failures of amyloid blocking molecules and antibodies in clinical trials. In some cases the agents have failed to clear the plaques, but tellingly in others, clearing the plagues did not put the disease in remission. Thus the scores of pharmaceutical companies that have several pipeline dwellers focused toward amyloid may be chasing an imaginary rabbit. There are serious concerns that scientists may have to go back to the drawing board and start all over again. This would be a huge setback.

However, hope need not be completely lost. One of the most reasonable explanations for the failure of these agents is simply that they arrived too late on the scene, when the disease had progressed too far to be defeated. Perhaps these drugs would have helped had they been administered earlier. Even cancers that can be treated if detected early fail to be cured in late stages, and AD should be no different. One of the big problems in the field is that detecting AD early is still a challenge and is being addressed by many promising neural imaging initiatives. Perhaps early and focused administration of these drugs could be successful.

Yet it all hinges on putting all your eggs in the amyloid basket. Another protein implicated in AD is tau, which forms tangles in the brain. But as the article says, targeting tau may be even harder than targeting amyloid since it is ubiquitous. Other processes hypothesized to be important for AD include oxidation and other neurotoxic processes of which amyloid may simply be a side-product. And as I was thinking this morning, perhaps no drug will ever be as effective in treating AD as a balanced lifestyle that includes preventive measures; and this may especially be true if amyloid is a natural part of our body's physiology. But as of now we have to keep on trying, and the amyloid hypotheis, shaky as it is, seems to be our best bet of making a dent into this devastating disease. At the very least it will lead to novel basic insights. Perhaps it's an indication of how primitive our understanding of the disease is that we continue to cling to amyloid. Under the present circumstances it seems to be the best we can do, but as another Churchillian admonition indicated, "it is not enough that we do our best; we must do what's necessary".

Indian village has unusually low rates of Alzheimer's disease

This caught my attention recently.

As the sun breaks through the morning mist in Ballabgarh, the elders of the village make their way to their regular meeting spot to exchange stories and share a traditional hookah pipe.

These men are in their sixties and seventies, while their faces bear the evidence of years of hard work in the fields, their minds are still sharp.

In other parts of the world, people of their age would be at some risk of developing dementia. But here, Alzheimer's disease is rare. In fact, scientists believe recorded rates of the condition in this small community are lower than anywhere else in the world.

Apparently the villagers here, mostly farmers, were tested for the ApoE4 gene which has been indicated as a risk factor for Alzheimer's. ApoE4 frequency was the same as in a population of farmers in rural Pennsylvania. Unfortunately the explanations suggested (vegetarian diet, lack of obesity, low cholesterol levels, physically fit farmers) does not seem to be unique to this farming community.

In contrast with lives in Pennsylvania and other parts of the world, the people of Ballabgarh are unusually healthy. It is a farming community, so most of them are very physically active and most eat a low-fat, vegetarian diet. Obesity is virtually unheard of.

Life in this fertile farming community is also low in stress, and family support is still strong, unlike in other, more urban parts of India.

"It all leads to a happy body, and a happy mind and hopefully a happy brain," says Dr Chandra. "Cholesterol levels here are much lower. We believe that is what is protecting the community."

There must surely be other farming communities in India and other places whose residents have a "happy body and a happy brain". I need to look up the original reference.