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 we will unravel in this volume, true Alzheimer’s disease is a continuum of events rather than a stepwise process. However, we need to break it up into definable steps for simplicity and to allow us to comprehend the progress of the disease. Figure 3.4 summarizes this continuum which will be explained here, with details of each topic forthcoming throughout this book. Essentially this figure includes information that has been covered up to this point and is simply presented in a different way to show the interrelationship between the topics we’ve been covering and to set the stage for some future topics.
Figure 3.4. The continuum of events in Alzheimer’s disease.
As mentioned above, the preclinical stage of Alzheimer’s disease is when the disease is set in motion but undetectable with today’s knowledge and technologies. The accumulation of amyloid beta and its coagulation or precipitation as amyloid plaques signals the early changes that are occurring in the Alzheimer’s brain. These lead to miscommunication between the neurons which is manifest as the loss of memory and other attributes that define “Mild Cognitive Impairment” or MCI. As the amyloid plaques continue to accumulate, a second culprit comes into play—tangles of fine filaments in brain cells called “neurofibrillary tangles”. As this is occurring, the signs and symptoms of Alzheimer’s are continuing to progress, along with major changes in brain structure. These include more serious and extensive miscommunication between neurons as well as the atrophy of the brain. These changes ultimately lead to dementia. So let’s begin our understanding of these events by covering mild cognitive impairment. In later chapters we’ll get into the nitty-gritty of amyloid plaques (Chapter 6) and neurofibrillary tangles (Chapter 7).
MCI: Mild Cognitive Impairment
Often the initial discovery of Alzheimer’s disease in an individual begins with that person’s concern about their perceived loss of memory. As we age, we all get concerned about the fact we can’t immediately recall details. We forget where we left our car keys or glasses. We can’t remember the name of a TV show. Our memory fails us in the middle of a story when a specific fact can’t be immediately recalled. All of this can make us think that we are losing our mind. When this concern becomes great enough, some of us (sadly not everyone) will go to a doctor, hoping for reassurance. In most cases, that reassurance is forthcoming. At other times it is not. This change in memory sometimes is an initial indicator that all is not well with, as Hercule Poirot put, “the little gray cells”.
As mentioned in Chapter 1 and above and summarized in Figure 3.5, aging can lead to forgetfulness that doesn’t progress or have anything to do with Alzheimer’s disease. On the other hand, some individuals will suffer from the disease at a young age, often well below age 65. Early-onset Alzheimer’s disease is discussed