Alzheimer’s disease: Cartels of forgetfulness

20. March 2014

Colombia has become the terrain of research for neurologists. In mountain villages of the region they come across unusually high numbers of patients with early Alzheimer's forms. This is where neurologists are testing innovative pharmacotherapies.

Antioquia, Colombia. The process of forgetting begins for many people already at the end of their fourth decade of life or even earlier. At an average of 47 years they reach the full stage – and there’s hardly a family that does not have to look after a critically ill patient. They all suffer from early Alzheimer’s forms, known as “Early Onset Alzheimer’s Disease”. Geneticists have found mutations in a significant number of the population in a gene that codes for a transmembrane protein belonging to the presenilin family. PSEN1 E280A, in abbreviated form, is historically and geographically associated with the Spanish conquistadors. Other mutations, for instance in the PSEN2 gene, are also known. In transgenic mice with the matching defect beta-amyloid peptides are found to accumulate in the brain – which is already a well-established fact. In Colombia, the hereditary defect located on chromosome 14 spread widely throughout clans over 300 years.This now attracts scientists to the region in order to learn more. By way of medical records and family trees they have long identified the particularly vulnerable families.

Amyloids – standing between a dead-end and hope

The basic problem: for a long time molecular biologists have been trying to succeed by working therapeutically against beta-amyloid peptides. However Francesco Panza, Italy, recently submitted a pessimistic summary. Together with colleagues, he researched the literature for clinical studies that deal with immunotherapies against harmful deposits in the brain. AN1792, a vaccine against beta-amyloids, led in six percent of all patients to meningoencephalitis and was withdrawn. Further phase III trials involving patients who were suffering from mild to moderate forms and received the humanised, monoclonal antibody bapineuzumab were also “disappointing,” comment the authors. And solanezumab, the next candidate, failed just as miserably in two phase III trials. Nevertheless, further studies provided, especially among patients with mild development of the condition, encouraging results. Active second-generation vaccines such as ACC-001 or CAD106 or Affitope AD02 were tested on high-risk patients who were not yet affected.

“Center for Preclinical Alzheimer’s Disease Research”

Now a prevention study using crenezumab is ensuring global attention. “The Lancet Neurology“ commented that Colombia has become the “centre for preclinical Alzheimer’s research”. It’s no wonder then that Colombian neurologist Francisco Lopera has kept on collating such data there for over 25 years. Currently, genetic information exists on 5,000 living persons. At present 300 subjects aged between 30 and 60 years who have as yet not shown noticeable symptoms are receiving either a placebo or crenezumab. Their risk profile had previously been determined by genetic testing. For the work required to be done the Banner Alzheimer’s Institute, Genentech and the U.S. National Institutes of Health provided around 100 million US dollars. If it turns out that the verum administered in the prodromal phase effectively prevents plaques, researchers would have made a breakthrough, without – as has been the normal course of events – having to wait for decades for results. In Antioquia neurologists only need to have the patience to wait for two to five years in order to get results, and possibly as it may turn out learn something that impells doubters of the amyloid hypothesis to think again. Ethical aspects is however something nobody wants to talk about.

Worse than expected

Behind the highly funded programs lie the concerns of many industrial nations of no longer being able to come to grips with Alzheimer’s. Recently researchers from the London Alzheimer’s Disease International calculated that the number of sufferers could triple by 2050 – from the current 35 million to 115 million. Not all scientists share the pessimistic forecast. According to Carol Brayne, who works at the Cambridge Institute of Public Health, the prevalence of dementia has generally declined over the last 20 years. Whether Alzheimer’s disease also falls into this group can however be subject to doubt, says Kaare Christensen from the Danish Odense. Doctors are continually succeeding in better coming to grips with hypertension and hypercholesterolaemia – and people are benefitting from better cognitive abilities into the later years of life. Alzheimer’s patients will obtain little from this. This is good enough reason for health ministers of the major industrialised nations and Russia to invest more money in research. The European Union agency, according to Health Commissioner Tonio Borg, has set aside 1.2 billion euros for use over the next two years in health research projects, including Alzheimer’s. Together politicians are hoping at latest by 2025 that the big breakthrough is made – it happening perhaps in Colombia.

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