More than a century has passed since Alois Alzheimer first described the case of Auguste Deter, a patient suffering from a profound loss of memory, delusions and rapid unpredictable mood changes. Alzheimer had seen the symptoms many times before but in patients much older than Deter, who first began suffering such symptoms in her forties. Alzheimer followed her case until her death in 1906 after which he dissected her brain and found dramatic shrinkage and deposits both in and around nerve cells. A few years later in 1910 the disease was finally named. Fast forward to 2014 and though we have made astounding progress in many fields of medicine that have given unprecedented insights into the causes and mechanisms of Alzheimer’s we are still no closer to a cure. That may be about to change according to a paper published in journal Aging recently.
A small trial conducted by the University of California Los Angeles and the Buck Institute for Research on Aging has reported a reversal of memory loss associated with Alzheimer’s.
The trial, which claims to be the first to show a reversal, consisted of only 10 participants and so will need to be followed up with a larger controlled study to either confirm or refute the findings. But it has to be said that the initial results raise an intriguing possibility, not least for the fact that this approach required no particular drugs or medications (though some were used). Simply, it consisted of lifestyle changes and dietary supplementation using readily available products.
The Drugs Don’t Work
“The existing Alzheimer’s drugs affect a single target, but Alzheimer’s disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well,” he said. “The drug may have worked, and a single hole may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much.” explains the paper’s author, Dr Dale Bredesen, in a press release accompanying the paper.
“The failure of treating neurodegenerative diseases with monotherapeutics,” Bredesen argues in the paper proper, “is the great failure of biomedical development.”
In the past decade hundreds of clinical trials have been conducted with combined costs measured in the billions of dollars and all without success.
In many other areas from HIV and cancer, to cardiovascular disease and osteoporosis improvements have been seen using a combination of therapies, yet comprehensive combination therapies haven’t been explored when it comes to Alzheimer’s.
This is particularly puzzling given that the last few decades of research into cognitive decline and Alzheimer’s have revealed that there isn’t simply one faulty mechanism at play, but a complex and intricate network of molecular interactions.
In the paper Bredesen lists thirteen different pathways and mechanisms that have been targeted in preclinical trials. Each trial, however, focused on just a single pathway and the large effects seen failed to be reproduced in human studies. The four reason he sets out why this might be so are
- In order to bring about an improvement it may be necessary to target multiple pathways simultaneously.
- It could be possible that a single pathway will be enough, but that much earlier intervention is required.
- It may also turn out that all the different pathways and mechanisms converge on a single critical pathway, so that either single target therapy or multi target approach may be effective.
- The possibility exists that neither a single target or a multi-target approach will work.
It may also be, he notes, that a multi target approach, even though the effect on each individual pathway is modest, has an additive or multiplicative effect. This idea is further elaborated upon in a earlier paper published in EMBO Molecular Medicine (1)
The paper advances the idea that Alzheimer’s is an imbalance in ‘endogenous plasticity signaling’. Brain plasticity simply refers the the ability of the brain to change, as it does, physically and chemically, throughout our entire lives.
In this respect, Bredesen argues, Alzheimer’s is analogous to other chronic diseases that result from a metabolic imbalance. Osteoporosis, for example occurs when osteoclastic (bone depletion) signalling exceeds osteoblastic (bone building) signalling. Using this analogy Bredesen suggests that with Alzheimer’s there is an age related imbalance between synaptoblastic and synaptoclastic activity.
Tied into this concept is the idea of positive feedback, where the imbalance selects and amplifies the disease process leading to the downwards spiral of progressive Alzheimer’s.
β-amyloid (beta-amyloid) is a protein fragment associated with Alzheimer’s. β-amyloid plaque build up in the brain is the relatively known cause of Alzheimer’s disease.
β-amyloid is a fragment of a larger protein known as the β-amyloid precursor protein (APP). Essentially, there are two ways in which APP can be broken down; one is amyloidogenic the other non-amyloidogenic. Amyloidogenic processing cleaves APP into four peptides – a peptide is a string of amino acids – β-amyloid(Aβ), sAPPβ, Jcasp and C31. These peptides bring about the retraction of links between neurons (neurites), inhibit synapses and activate programmed cell death. The non-amyloidogenic processing of APP, however, produces two peptides sAPPα and αCTF. sAPPα and αCTF are responsible for neurite extension and inhibit both Aβ production and programmed cell death.
Consequently APP is thought to function as a molecular switch controlling brain plasticity. Alzheimer’s is associated either directly or indirectly with an increase in ratio of neurite-retractive peptides to the neurite-extending peptides. a number of studies have shown that reducing this ratio by preventing the cleaving of APP to form β-amyloid can lessen the severity of Alzheimer’s disease.
Bredesen’s hypothesis is that Alzheimer’s is the result of this positive feedback or prionic loop. The cleaving of the APP protein to produce β-amyloid creates a self amplifying cascade effect, whether via β-site APP cleaving enzyme (BACE) or some other mechanism. Conversely, the binding of a trophic ligand – a protein that stimulates growth, survival etc – increases the production of sAPPα, which in turn inhibits BACE, whilst sAPPα’s corresponding fragment, αCTF, blocks γ-secretase (gamma-secretase); an enzyme involved in cleaving APP and generating β-amyloid.
Essentially, cutting APP at the α-site produces fragments that inhibit the cleavage of the β and γ sites thus protecting against Alzheimer’s. Cleavage at the β and γ, however, makes β-amyloid and C31 which is pro-Alzheimer’s.
Studies using transgenic mice suggested that not only was APP fundamental to brain plasticity, but that various mutations in a type of mouse used to model Alzheimer’s could prevent the usual synaptic loss, memory deficits and atrophy that are associated with the PDAPP mouse model.
These mouse studies, in turn, suggested that the APP positive feedback loop could be manipulated to prevent Alzheimer’s. The mice models, however, had mutations in APP and other genes related to early onset Alzheimer’s; a type of Alzheimer’s that only affects 5-10% of those who suffer from the disease. The vast majority of cases are sporadic and don’t have mutations in APP or lack other genes modelled in the mouse studies.
One Piece of the Puzzle
The mechanism outlined above has many contributing inputs and, important though it is, the contribution of APP and β-amyloid is just one part of an extensive network of pathways involved in Alzheimer’s.
With so many pathways and mechanisms at play and the lack of success with monotherapeutics, logic would dictate that an multi-target approach would be the next step.
With this idea in mind Bredesen and colleagues formulated a therapeutic system.
In the next post I’ll outline the details of the system Bredesen employed and take a look at some of the case studies he described.
Following some feedback I put together a streamlined post which details the interventions used in the study.
For a more in depth look at the rationale behind each intervention follow the links below
Bredesen DE. Reversal of cognitive decline: A novel therapeutic program.Aging (Albany NY) 2014;6(9):707-717. (pubmed link)
The APP cleavage diagram is taken from the source paper cited above.