Thursday, July 30, 2009

Malleus Amyloidarum

If you are passing familiar with the subject of Alzheimer's disease (AD), you have certainly heard of amyloid. Almost everybody in the field will tell you that amyloid is that toxic gunk which clogs up cellular machinery and kills cells causing AD. And everybody is wrong.

It all started with a case of early-onset dementia described by Alois Alzheimer who noted the presence of red-staining material in post-mortem examination of his patient. Alzheimer wrote that the patient was clearly different from the usual senile dementia cases by clinical criteria such as age of onset and duration but later other researchers observed that the same material was also more frequently present in the brains of elderly dementia cases. Somehow, this persuaded them that these different clinical presentations must be one and the same disease - probably under the influence of the infectious disease paradigm, where finding the same pathogen in different locations did not alter the diagnosis of, say, tuberculosis. But, in medicine we frequently see similar images in diseases with completely disparate mechanisms - for example, one will find a lot of similar-appearing immune cells during an infection (where they help combat the pathogen) and in autoimmunity (where they actually cause the disease). In the absence of a good understanding of the specific condition it is unwise to commit oneself to one or the other interpretation of histopathological data.

Fast forward a hundred years - It is commonly accepted to refer to non-familial senile dementia as "Alzheimer's", still in the absence of any understanding of the relationship between the familial (genetic) and sporadic cases. The molecular biology revolution brings early fruit - explanation of the cause of Huntington's disease, where a mutated gene starts producing gunk not unlike amyloid although in a different location. An ambitious research program is formulated by "Alzheimer's" researchers - to use genetic approaches to elucidate the cause of familial AD and thus provide an explanation of the much more common sporadic cases (We "know" they are one and the same, don't we?). Stunning success follows - the APP (amyloid precursor protein) gene is found to be abnormal in a few families with AD! The product of APP, or beta-amyloid, is a major component of the amyloid plaques found in both familial and sporadic cases! If amyloid is added to neural cells in culture, they die! As Mr Gore would have said if he was into dementia research, "The science is in!" Case closed.

Now all we need to do is to tie up some loose ends, and find a method for removing amyloid from brains, and presto, we have a cure for senile dementia. Nobel prizes and profits will follow.

So hundreds of millions, and later billions of dollars pour into amyloid research. One of the loose ends is finding mutations in the APP gene in sporadic cases of senile dementia. Yet, here a setback occurs - not only such mutations are not found, it is definitely proven that they are absent. For anybody with a background in genetics (like me), this is a major red flag - you have one condition, early-onset AD, *with* a mutation, and a similar but clearly clinically different condition, late-onset sporadic "AD", *without* the mutation. The geneticist will automatically conclude that these are different diseases with some superficial similarities, rather than slightly differing manifestations of the same disease. But, the Baptists (the Beta-Amyloid-Protein people) cheerfully press on with their research.

Attention is directed towards demented mice. It's hard to do research on demented old folks, one needs something simpler, like a mouse with a mutation in the gene analogous to the one that is damaged in demented humans. Considerable resources are brought to bear, and here follows a disappointment - mice with APP mutations do not develop dementia :(

Well, never mind - let's make a mouse with not only an APP mutation but also a mutation from a different form of early-onset AD, the presenilin-1 mutation, and for good measure, a mutated tau protein from yet another familiar disease, frontotemporal dementia. Success! Mice develop deposits of amyloid and get sick. As the venerable Nature Medicine writes "A transgenic triple scores a home run". An outside observer might start asking - You are using a mouse slapped with three abnormal genes from three different human inherited diseases as a model of a sporadic disease *proven* not to be caused by mutations in any of these genes? Are you sure it's a good idea?

We are sure, to the tune of many hundreds of millions of dollars poured into methods for getting rid of amyloid. There are drugs that inhibit processing of the APP, and there is a vaccine to stimulate the removal of amyloid from brains. Unfortunately, patients treated with these nostrums don't get better. In fact, after the amyloid vaccine some develop encephalitis (brain inflammation) and the trials have to be stopped. Oh, the high-flying stock of Elan Pharmaceuticals, a fleeting memory.

On top of that there are all these pesky observations that accumulated over time - e.g. the fact that the concentration of amyloid needed to kill cells in culture is actually never observed in the brains of humans, demented or otherwise. Or the fact that actually there are millions of elderly with a senile dementia without any significant amyloid yet clinically indistinguishable from the amyloid-laden cases. And conversely, there a millions of elderly without a trace of dementia but with a lot of amyloid. Or the finding that the concentration of soluble amyloid in the cerebrospinal fluid does not correlate with dementia, in fact, it seems like more amyloid may mean less dementia. Or the observation that neurons close to amyloid plaques are actually healthier than neurons located farther away from them. And finally, the finding that the only drug that seems to slow down the progression of senile dementia, dimebon, actually *increases* the concentration of amyloid in mouse brains.

Isn't it about time to reject, repudiate and renounce the amyloid hypothesis of "AD"? I know it's difficult to say that 20 years of work by 95% of scientists involved in the senile dementia field is useless. Or that concentrating all resources, without good rationale, against early warnings from genetics, on a speculative explanation for dementia has certainly delayed finding its real cause.

But isn't this the scientific thing to do?

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