Thursday, 9th of December to Sunday, 12th of December 2010

Dear colleague,

During the last 8 years we discussed at our Zuers Winter Conference different approaches to treat Alzheimer's disease, but unfortunately many of the compounds, which looked extremely promising only a couple of years ago failed in the meanwhile to show efficacy in phase III clinical trials. So last year we intensively discussed already “Why do we have so few drugs to treat Alzheimer's disease?”. We came up with different reasons like appropriate study design, patient populations, wrong targets and potentially some not well characterised drugs, which entered advanced clinical trials without clear efficacy signs in early clinical development.

In the meanwhile additional drugs addressing beta amyloid toxicity have failed to show efficacy in clinical studies. Therefore the discussions centered around the question if potentially Abeta has already done such substantial damage until first symptoms of AD show up that it is impossible to reverse the condition, that it is even difficult or impossible to stop the progression. This certainly advocates to start therapeutic intervention at very early disease stages, certainly in a pre-symptomatic stage.

There was ground breaking work done by Bruno Dubois and colleagues of him to define new diagnostic criteria for early AD based on clinical evaluation, imaging and biomarkers. More and more data are supporting these new diagnostic criteria to be relevant for selection of patient populations for therapeutic trials, in spite that so far not a single trial in this population has been published. Anyhow these attempts changed within a very short time our understanding of the diagnosis of Alzheimer's disease as well as the thoughts about design of therapeutic clinical studies.

Now, in this year we want to discuss about the validation of the new diagnostic criteria of AD, and highlight if enough data have been already accumulated to enable us for reliable testing of new drugs in that patient population. How can we support the clinical diagnoses with more sophisticated and sensitive neuropsychological testing scales? What is the significance of computerized testing batteries and to which extent they can not only help for diagnoses but also be used as sensitive tools to pick up drug efficacy? More than the application of advanced imaging techniques is needed for a reliable diagnoses of early disease stages. We have now years of experience with in vivo amyloid staining using the Pittsburgh compound (PiB), indicating amyloid accumulation in pre-symptomatic subjects. At the same time the longitudinal investigations in AD patients also showed that in later disease stages the correlation with functional decline is pure. Is this again indicating that the initial accumulation already did widespread damage to the brain? On the other hand a few studies with treatment approaches like passive vaccination indicated at least that it is possible to measure treatment dependent amyloid reduction in the brain of patients. Attempts to refine amyloid imaging have been made and we want to discuss at our conference new more advanced techniques. They should also help to get a more widespread use of amyloid imaging in the clinical practice. But what is the significance of other technologies like structural MRI documenting the progression of brain atrophy or functional MRI for documenting early changes in memory and learning dependent neuronal circuits? To what certain extent are all dimensioned technologies correlated? Is there one of them superior to the other, do we need combination to confirm diagnoses?

Of course there are also international efforts to define reliable cerebrospinal fluid (CSF) and blood biomarkers. Lot of progress has been made by different initiatives, spear-headed by Kaj Blennow and his team to standardize and validate determination of amyloid beta peptides and tau protein. Based on this work it is possible to establish diagnostically meaningful patterns of different biomarkers in CSF which can certainly be useful for confirming the clinical diagnoses of AD. But is it also possible to develop new blood biomarkers? How progressed are we with these techniques already? How reliable they are, how many false positive and false negative data we are creating? How can we use these markers for documenting drug effects?

Of course we also want to dedicate a significant time to new drug developments in that field, and now addressing to which degree they might particularly useful in treatment of early disease stages. Based on the amyloid cascade theory certainly therapies addressing reduction of amyloid at different levels of aggregation including toxic oligomers is in the focus of interest. This time we will particularly discuss in active and passive immunotherapy because it is evident that vaccination against these toxic peptides would be suitable as an early intervention, which could also potentially provide long-term effects. What are the pros and cons of these therapies? Do we know already enough to make a reliable judgement on long-term safety? What can we conclude from past and ongoing clinical trials with that treatment approach? How shall we direct clinical research with immunotherapy of Alzheimer's disease in the future?

But of course there are also many other possibilities to influence the occurrence of amyloid beta peptides in particular Abeta 1-42, including gamma secretase modulators and gamma secretase inhibitors, beta secretase inhibitors or any other compound that interferes with the synthesis of APP and its processing. So we will have plenty of room for discussions here. It is almost logical that other pathological hallmarks of the disease like tau protein or frequently occurring alpha synucleinopathy which can be associated with Alzheimer's disease is of interest. Therefore also treatment approaches addressing these pathogenetically important proteins will be included. Finally small molecules will still play a role in direct interference with important cellular signalling pathways or with neurotransmitter signalling. Also here plenty of promising developments are on the way.

This year the conference starts on 9^th and ends on 12^th of December 2010. It will take place in the village Zuers, which is located on the Arlberg, one of Austria’s best skiing resorts. The conference will take place in the hotel Albona Nova, a small family style hotel with exceptional cuisine, helping us all to recharge our batteries after lively scientific discussions (skiing during lunch break is not excluded). The meeting is limited to a maximum of 80 participants because we want to achieve a high level of discussion and networking. The regular fee for participants is 950 € and it includes the registration fee, accommodation for three nights and all the food (for accompanying persons the fee is 450 €).

I am convinced that this year again we will have quite a stimulating discussion about advantages and risks in drug development for early Alzheimer's disease. I am looking forward to hearing from you and hopefully welcoming you in Zuers beginning of December!

On behalf of the organizers,

Yours sincerely,

Dr. Manfred Windisch