Читать книгу The Alzheimer's Epidemic - Danton O'Day - Страница 25

Since Alzheimer’s disease starts long before there are any overt symptoms, this makes the search for causes and a cure much more difficult. Figure 3.1 provides a simple summary of how the as yet undetermined initiating events precede the presymptomatic phase. As its name implies, a person shows no symptoms during the presymptomatic phase. The presymptomatic phase is followed some time later by the actual symptoms of the disease where initially observed cognitive deficiencies often progress over time. As we will learn, there are some known predictors of Alzheimer’s disease. There are certain genes that are linked to the disease, for example, but the actual initiating events that drive the onset of the disease are not known.

Figure 3.1. The onset and progression of Alzheimer’s disease.

So, after the ground has been laid for the disease, it is followed by a long presymptomatic phase where the person appears completely normal and exhibits no cognitive deficiencies. Their memory is good, they recognize friends, family and items; they relate to the world around themselves. But during this time changes in the brain are occurring which will alter how their brain cells talk to each other. This progressive failure in brain cell communication underlies the events that will define the symptomatic phase, because without normal brain cell intercommunication, cognitive deficiencies become evident which usually can progress to greater brain malfunction.

The goal of biomedical research, and the underlying focus of this volume, is to study the progression of Alzheimer’s disease from the events that initiate it through to the final changes that face individuals who develop full-blown dementia. As summarized in Figure 3.2., by asking and answering specific questions at each stage, not only can the disease be better understood but new therapies can be developed. For example, by answering the question, “How does the disease start?” researchers will ultimately answer the question of how to cure the disease. The value will be the ability to stop the disease before it starts. This, of course, is the most challenging issue. After all, how can you study something that apparently hasn’t happened yet?

Knowing what happens in the presymptomatic phase prior to the onset of cognitive deficiencies will allow biomedical researchers and pharmaceutical companies to find ways to slow or prevent the progress of the disease. Of course, the problem is determining when that phase exists when there are no symptoms that are evident. This is where the role of biomarkers comes into play as detailed in Chapter 11. Dissecting out the underlying brain changes that precede the onset of mild cognitive impairment will reveal targets that can become the focus of interventions aimed at slowing or stopping the progress of the disease.

Figure 3.2. Asking and answering questions about the onset and progression of Alzheimer’s disease. MCI, mild cognitive impairment.

Figure 3.3 summarizes these events, relating them to the underlying changes that are occurring in the brain and the specific stages of Alzheimer’s disease. As we progress through this volume, we will learn more about each of these topics. There are known underlying brain changes that occur during Alzheimer’s disease. While the actual initiating events and underlying biochemical changes are not known, during the presymptomatic phase, a substance called amyloid beta begins to accumulate (Figure 3.3., top). As mentioned in Chapter 1 and detailed in Chapter 6, amyloid beta peptides will accumulate to form amyloid plaques, one of the hallmarks of Alzheimer’s disease. As this occurs the disease is progressing into the mild cognitive impairment stage of the symptomatic phase (Figure 3.3., bottom). Neurofibrillary tangles (NFTs; Chapter 7) begin to form and, coupled with the amyloid plaques, lead to progressive neurodegeneration that is linked to brain cell miscommunication and death. These events begin to transform the symptomatic phase from the mild cognitive stage to dementia as detailed later in this chapter.

Figure 3.3. Events and changes linked to the onset and progression of Alzheimer’s disease. Aβ, amyloid beta; NFTs, neurofibrillary tangles; MCI, mild cognitive impairment.

In support of this model, a study published at the end of 2012 in Lancet Neurology revealed that the appearance of amyloid beta occurs during the presymptomatic phase long before there are any overt symptoms of the disease. As the disease progresses, amyloid plaques form from accumulations of amyloid beta and other components. The accumulated evidence argues that the appearance of plaques is followed by another hallmark of Alzheimer’s disease, the formation of neurofibrillary tangles (NFTs). Working on both the outside (plaques) and inside (tangles) of nerve cells, these accumulations begin to affect how nerve cells talk to each other. One might say the plaques gum up the surface of nerve cells where they contact and send messages to each other, while the tangles interfere with events inside these cells where the messages are translated and prepared to be sent on to other cells.

As the plaque and tangle populations continue to grow, nerve cell communication becomes severely compromised. The result is a progressive loss in one’s ability to routinely reason fully or recall names and events, among other things. In the early symptomatic phase, this mild cognitive impairment (MCI) is often noticed by family and friends, if not the individual themselves. As the brain cells begin to deteriorate and die, MCI can progress to full-blown dementia where the person will fail to recognize or be able to relate to friends, family or the world around them.