Alzheimer’S Disease: Fundamental Research Paves The Way For Therapeutics.

Alzheimer’s disease: fundamental research paves the way for therapeutics.

Introduction: biotechnology’s ambitious goals

Until recently, the discovery of a successful drug wasn’t actually the logical end point of the elucidation of a disease process. Rather, it was dependent on major doses of luck and coincidences. One speaks of �serendipity’: �the effect by which you accidentally discover something fortunate, especially while looking for something else entirely’. A world-famous example is Fleming’s discovery of penicillin as a treatment for infectious diseases. Upon returning from a holiday, he realised he had not cleaned up his bacterial plates before leaving. When he took them out, he noticed a strange thing: fungus had grown on the plates and killed all the bacteria in its vicinity. Fleming deduced that the fungus produced an �antibiotic’ substance and went on to isolate it.

Modern biotechnology asks for a more rationalistic approach: the development of a drug should be explicitly based on a thorough understanding of the molecular mechanisms that cause a specific disease. The billions of dollars and euros that annually flow into pharmaceutically oriented biotechnological research can only be justified if this rationalistic approach bears fruit. Using recent developments in fundamental research on Alzheimer’s disease as an example, we will evaluate whether biotechnology lives up to its promises.

Alzheimer’s disease: a two-level definition

Without doubt, Alzheimer’s disease is one of the major medical challenges of our time. So far, there is no medication that significantly alters the course of the disease. Its incidence is rising rapidly in all developed countries because of the disproportional increase of the aging population. Belgium alone contains 70,000 Alzheimer’s patients; in the United States there are 4 million of them. Taking care of Alzheimer patients is not only a major burden for the relatives, it also forms an enormous socio-economic cost that threatens to undermine our social security system. According to an estimate by Professor Pacolet of the University of Leuven, the total cost of care (including medication and nursing) amounts to 1,970 euro per week, per patient.

A clinical definition of Alzheimer’s disease

One way to define a disease is by describing the symptoms it causes. In the case of Alzheimer’s, a specific complex or set of symptoms develops that goes by the name of вЂ?dementia’, and which is closely associated with the aging process. Initially, the only conspicuous feature is problems with short-term memory вЂ" the patient has difficulties learning and remembering new information, such as the name of a newly born grandchild. But this seemingly innocent problem develops into complete memory dysfunction, meaning that older, already stored information is also lost. In due time, the patient no longer recognises family members, friends, or their own daily environment. Simultaneously, other cognitive functions deteriorate: the understanding and use of speech, the use of utensils, emotionality, etc. In the advanced stages of the disease, one can say that the whole personality structure of the patient has been wiped out вЂ" hence the name вЂ?de-mentia’ (mens being Latin for mind).

A neuropathological definition of Alzheimer’s disease

A second way of defining the disease is by describing exactly what happens to the patient’s brain tissue. This definition will be more concise, since the symptoms of dementia can be caused by a host of other disease processes besides Alzheimer’s. Blood vessel constrictions or haemorrhages in the brain tissue, which impair the nutrition of brain cells, leading to their demise, or certain infectious agents such as HIV can all lead to dementia. But its most frequent cause is still the collection of brain abnormalities we refer to as �Alzheimer’s disease’.

In 1906, the Bavarian neuropsychiatrist Alois Alzheimer (Figure 1A) was the first to provide us with a clear account of the nature of the damage that is caused in the brain by the disease that from then on carried his name. He had performed a post-mortem investigation of the brain of one of his former patients, Auguste D (Figure 1B). He had been her clinician since she first came to him, five years previous, at the age of 51, announcing that “she had lost herself” (in the early stages of the disease, a certain recognition of one’s own developing memory dysfunction is often still possible). Alzheimer correctly identified the three types of lesions that, up to this day, are used to make a definitive, 100 percent certain diagnosis of the disease; albeit, of course, post-mortem, in an autopsy. The first criterion is the loss of total brain volume due to massive death of neuronal cells. This is what explains the disease’s symptoms: memory, the ability of speech and emotionality are in essence functions of specific brain circuits composed of neuronal cells. The second criterion is the widespread presence of the so-called вЂ?amyloid plaques’. These are microscopically small deposits of a white substance called amyloid, in between brain cells. Although, for historical reasons we shall not go into, this is derived from amylum, which is Latin for starch, amyloid is composed of proteins instead of sugars. The third criterion is the presence of вЂ?neurofibrillary tangles’ (NFTs): tiny, dark-coloured collections of fibers within affected neuronal cells. These tangles are also composed of protein building blocks (Figure 2). Alois Alzheimer took a visionary approach: he tried to explain changes or abnormalities in behaviour and mind by physical lesions in the brain. At the beginning of the 20th century, this was far from self-evident.

Creeping forward during the pre-biotech era

During the eight decades following Alzheimer’s account, �old school’ scientists tried to find out more about the nature of the plaques and tangles, but relatively little progress was made. Three lines of research produced work of lasting importance. The advent of the electron microscope (EM) in the 1950s and �60s made it possible to describe the structure of plaques and tangles in astonishing detail, though their molecular composition could not be resolved. Secondly,

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