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.
How Does Alzheimer’s Start?
What is the trigger for this devastating disease? This is the big question. It will also be the most difficult to determine. If we are ever going to prevent Alzheimer’s disease from developing, we need to know when it actually starts. What is the trigger? Is it a single event or many simultaneous or temporally defined events? Is it the same for all cases or are there many initiating causes that vary from individual to individual? At the very least it will be critical to know the earliest, if not the first, changes that underlie the onset of the disease. Knowing how Alzheimer’s initiates and progresses will allow biomedical scientists find ways to prevent, ameliorate and ultimately cure the disease.
The results of a diverse number of studies, meetings and conferences suggest that the underlying events of Alzheimer’s disease occur long before the disease becomes evident. As summarized in the previous paragraph and indicated in Figure 3.3, the initiating events (cause or causes) that set the disease in motion are unknown. The same goes for the number of years it takes for the resulting changes to take hold. However, some advancement has recently been made in this area. The initial underlying but unknown changes in the brain are believed to be the pathophysiological underpinnings of Alzheimer’s disease. They presage the clinical aspects of the disease. As mentioned, there is a long asymptomatic phase or latency period between the pathophysiological changes that occur in the brain and the clinical aspects which we see as Alzheimer’s. During the latency period or presymptomatic phase, amyloid beta builds up in specific brain regions, transforming a person without symptoms into one who shows symptoms of cognitive impairment. Until very recently, scientists suggested that there was around a 10-year latency period before the cognitive effects of Alzheimer’s become evident. With that timeline extended to as much as several decades, it opens up a much wider window for early diagnosis and therapeutic intervention. But what are the targets for diagnosis and intervention?
Investigations into the early events in Alzheimer’s are focusing on potential biomarkers for the disease which will permit early diagnosis—the first step in being able to devise a cure in the long term and in helping the patient fight the disease in the short term. In short, current approaches to dealing with Alzheimer’s disease are taking the same approach used for other diseases such as heart disease, diabetes and cancer, to name a few. For example, with heart disease, it has been shown that high LDL (low-density lipoprotein) is bad. So doctors help individuals lower the amount of this bad form of cholesterol in their blood by regulating their diet and/or prescribing medicine. If the causative agent of Alzheimer’s disease, assuming there is one or at most a few, could be determined, then the quest for a cure is possible. Alzheimer’s, however, may be more like cancer where multiple causes lead to multiple forms of the disease in a diversity of human tissues. Since the brain is the primary tissue of assault in the disease, then it is believed the cause or causes may be few in number but that is yet to be learned.
Thus the presymptomatic stage—the stage when no symptoms are evident—is a stage when the events of Alzheimer’s disease are set in motion likely in part by the accumulation of amyloid beta. This is also called the preclinical stage because there are no symptoms that can be identified by a clinician. The changes that are occurring are happening at the cellular level, in the brain neurons where all thinking and reasoning occurs. Later we’ll look at some work that is being done to identify attributes of the preclinical or presymptomatic stage that will allow for early detection and intervention. Identifying these changes could one day point to the initiating events of the disease which in turn may provide hope for a cure.
Personality Changes Can Be a Signal
As we age, significant changes in personality can be a signal that something is amiss with our brains. Or as a doctor might say, “Significant behavioral changes might be indicative of an underlying neurological disorder”. Thus, changes in how a person interacts with others or behaves in the presence of others might indicate neurological changes linked to mild cognitive impairment. Similarly, when an individual starts to act differently in normal surroundings or shows deficiencies in how they deal with the activities of normal daily living, then negative neurological changes might be occurring. It is important to determine that these kinds of changes aren’t due to non-neurological stresses such as family strife, breakups, financial difficulties or the multitude of daily stressors we all face in life and which affect how we behave. Having used the term “mild cognitive impairment” several times already, let’s take a look at what this means because it is a key early stage in the progression of Alzheimer’s disease.
As
