Research on Alzheimer’s disease: the bad news, the good news

The past few months have seen a flurry of work on Alzheimer’s disease.  The news has been both good and bad.  First, some background for the nonMds.

Just as the gray hair on the head of an 80 year old looks the same under the microscope as one from a prematurely gray 30 year old, the brain changes of Alzheimer’s disease are the same regardless of the age of onset.  Alois Alzheimer described the microscopic changes in a youngish person so initially the disorder was called presenile dementia.

There are basically two distinctive changes (1) senile plaques outside neurons (2) neurofibrillary tangles inside neurons.  Note that common to all dementias there is a severe loss of neurons, so something is killing them.   The major protein component of the senile plaque is a 40+ amino acid peptide called the Abeta peptide.  It is a fragment of a much larger protein (the amyloid precursor protein which comes in 3 forms containing 770, 751 or 695 amino acids).  The major protein component of the neurofibrillary tangle is hyperphosphorylated tau protein.

Thinking about pathologic changes in neurologic disease has been simplistic in the extreme.  Intially both plaques and tangles were assumed to be causative for Alzheimer’s.  However there are 3 possible explanations for any microscopic change seen in any disease.  The first is that they are causative (the initial assumption).  The second is that they are a pile of spent bullets, which the cell used to defend itself against the real killer.  The third is they are tombstones, the final emanations of a dying cell.

Large battles have occurred about the causative roles of tau and Abeta in the Alzheimer’s disease.  As usual, the best evidence is genetics, as there are mutations in these proteins associated with dementia running in families.  Please note that most Alzheimer’s and most dementias are NOT hereditary.  The evidence for Alzheimer causation is strongest for the Abeta peptide and its parent the amyloid precursor protein.  25 of 30 known dominant mutations in the amyloid precursor protein (APP) are associated with Alzheimer’s disease. Over 200 mutations are known in APP and the proteins which process it to Abeta [ Neuron vol. 68 pp. 270 – 281 ’10 — this has a link to an updated database of mutations ].

So an obvious attack on Alzheimer’s disease is to reduce the amount of Abeta present in the brain.   This is unlikely to be curative, as human neurons (as opposed to animal neurons) don’t regrow — the evidence for this is quite good despite publicity to the contrary — See Neuron vol. 74 pp. 595 – 596, 634 – 639 ’12 and references therein.  However, to stop the disease in its tracks wouldn’t be bad at all.

One approach would be to get rid of the accumulated Abeta peptide in the brain. Here’s some bad news.  Unfortunately a trial of antibodies against Abeta, just reported didn’t work.

For details see  Be sure to read the comments as they are interesting.  There is a lot of discussion of the fact that antibodies are large proteins, which don’t get into the brain  very well (if they get in at all). Also they didn’t see how antibodies would mobilize what is basically the insoluble gunk of the senile plaque.  So this doesn’t damn the idea of lowering Abeta as a way to slow the disease, just the way they did it.

In fact there is an interesting animal model based on a Ayurvedic medicine preparation (yes Ayurvedic medicine !), which DID reduce Abeta peptide in mouse brain.  The animals were said to be getting smarter (but mouse smartness has never impressed me).  The intriguing point is that the reduction occurred by chewing up Abeta in the liver, implying that to work the drug doesn’t have to get into the brain.  Presumably, by le Chatelier’s principle even the most insoluble gunk is in equilibrium with a small amount of soluble material.  For details see

A second approach would be to stop the Abeta peptide from forming.  Since it is a 40  – 42 amino acid fragment of the much larger amyloid precursor protein, an enzyme (a protease) must be breaking APP down to form it.  Actually there are 3 enzymes known which break down APP.  They are called secretases, because most of APP lies outside the cell, and when it is cleaved, part of the protein is secreted.  It would be great if all we had was alpha secretase, as this breaks down APP  right in the middle of Abeta, so it is never formed.  Actually it wouldn’t great at all, because one of the other enzymes — gamma secretase, breaks APP in the middle of the membrane, and the part remaining in the cell (called AICD) has important work to do.  At any rate lots of work is in progress on beta and gamma secretase inhibitors, but impressive results aren’t to be found as yet.

The failure of trials to lower Abeta peptide has led to some doubt as to whether Abeta peptide is really the killer of neurons.  This is where the good news comes in.

Here’s a summary, but the print editorial and paper can be found in the 2 August ’12 Nature (vol.  388 pp.  38 – 39, 96 – 99 ’12).  The quick and dirty is that a mutation has been found in the amyloid precursor protein which PROTECTS against Alzheimer’s disease.  The authors sequenced the APP gene of 1,795 Icelanders, just to look for low frequency variants.  A mutation was found 1 amino acid away from the site cleaved by beta secretase (it changes amino acid #673 from alanine to threonine (written A673T).  When the protein is cleaved this becomes amino acid #2 of the Abeta peptide.

The mutation is far from common — around 1/200 in Scandinavian populations, and even lower in a more heterogeneous North American population.

Then they looked at two groups of people — those with and those without Alzheimer’s disease.  5 times fewer people with Alzheimer’s disease 1/1000 had the mutation than those without, so the mutation in some way is associated with protection against the disease.

What’s going on?  A study in isolated cells shows that the mutation is associated with a 40% reduction in the formation of Abeta peptide from APP.  This makes sense. A different variant at this position (alanine to valine) INCREASES Abeta formation, and is associated with Alzheimer’s.  So this is excellent evidence that APP and Abeta are involved in Alzheimer’s disease.

The news gets better and better, the (rare) variant increased the odds of reaching 85% by 50%.  Then they studied people over 85 living in nursing homes.  41 carriers of A673T had better cognitive function that 3,673 non carriers.

So this gives a lot of hope to the decrease Abeta and slow down or prevent Alzheimer’s disease hypothesis and therapies aiming to do so.  Whether or not doing this in people who’ve already begun to decline from Alzheimer’s disease will be helpful isn’t known.  

Nonetheless, hope in this awful disorder is always welcome.

Now for a social note:  When a study shows a particular therapy doesn’t work, the approach is abandoned.  Not so for therapies targeting society at large.  The war on poverty is now nearly 50 years old, and a recent story said that the incidence of poverty (as currently defined) is approaching a level not seen since the 60’s–

As far as I can tell, there have been no calls to abandon the current approach, and try something else.  Changing it will be difficult, I have several family members that poverty has been very good to.  They work in various social agencies to help the poor.  They live quite comfortably.

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  • Michael Gold, MD  On July 26, 2012 at 5:54 pm

    The finding that a mutation in the APP gene can be protective against AD is quite interesting. The putative mechanism (reduction in BACE cleavage) is a mechanism that many drug companies have been working on for many years and we have yet to see viable and safe BACE inhibitor pass a phase II study. We all need to keep in mind that this mutation has been at work the entire lifetime of people who carry it, so one has to be cautious in expecting that reducing a-beta production would have any effect on people who have been accumulating it for 50 years. The result the serial failures of compounds targeting a-beta (tramiprosate, flurizan, AN-1792 and now bapineuzumab) has led some to conclude that the problem is that treatment is being started too late. While this is a plausible and testable hypothesis (albeit one fraught with serious issues), one has to also keep in mind an alternative hypothesis, namely that in sporadic, late-onset Alzheimer’s Disease, a-beta deposition is not causal.

    • luysii  On July 26, 2012 at 7:02 pm

      Couldn’t agree more with the idea that, probably like atherosclerosis, Alzheimer’s is a process that begins early and doesn’t cause symptoms for decades. The Korean war autopsies on 19 – 25 year olds showed that most had the early lesions of vascular disease (e.g. fatty streaks in the aorta, etc. etc.). As you say, treatment in the sense of prevention might have to begin quite early.

      It might be that the plaques, if causative, once present continue to wreak havoc, in which case stopping more of them from forming might not be beneficial. However, consider my college classmate, and former head of fairly large county medical society. He’s been deteriorating for 11 years now. Keeping him the way he was 5 years ago by arresting the disorder would be quite worthwhile.

      It’s also worth noting that synapses in the living brain are far from fixed, and are always moving around (in animals at least). For details see another post for some references on this point. The plaques might simply be getting in the way of new synapse formation

      Thanks for commenting

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  • By How to Understand Disease on July 26, 2012 at 2:12 pm

    […] A Bunny (( ( – -) ((‘) (‘) Mouse here for Related LinksResearch on Alzheimer’s disease: the bad news, the good news This entry was posted in Health And Fitness and tagged disease environment, how to understand […]

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