way by a process called “programmed cell death” (or, to use the appropriate scientific term, “apoptosis”) that will be discussed later in the book. Brain cells are also killed throughout life. The death of brain cells is important in the building of the connections between them that define how our brain operates. This cell death also removes cells that are not essential for these normal brain functions.
With Alzheimer’s disease, brain cell death is a concern because, unlike normal cell death in brains, it is uncontrolled and it occurs at an alarming rate over an extended period of time. Good brain cells are killed off indiscriminately. For now, we’ll talk in generalities about the two major reasons why this occurs. Both of these reasons involve proteins (Figure 1.4). One of the reasons is the buildup of plaques outside of and between brain cells, a hallmark of Alzheimer’s disease discovered by Alois Alzheimer. These plaques are made up of proteins of which one is the primary culprit. This very small protein culprit is called “amyloid beta”. Actually, since it’s a relatively short sequence of amino acids, it more correctly is called a peptide as detailed in Chapter 6. The amyloid beta peptide is secreted in large amounts by Alzheimer’s neurons but not normal brain cells. Outside the cells, amyloid beta accumulates in plaques, large protein masses that surround brain cells and interfere with their function and survival. As a result, there is a direct correlation between the appearance of the protein in these plaques and the process of neurodegeneration.
Figure 1.4. Protein deposits in the Alzheimer’s brain. Plaques of amyloid beta peptide accumulate outside of brain cells, while neurofibrillary tangles made of tau protein localize inside them.
The second culprit that Alois Alzheimer identified is the fine tangles inside of the neurons of Alzheimer’s brains. Like disorganized tangles of thread, these protein masses work inside of brain cells to negatively alter their function. The protein involved is tau, like the Greek letter. Tau works in normal cells but when large amounts accumulate and it is modified, as we’ll discuss later in Chapter 7, it forms filamentous masses called neurofibrillary tangles.
So you might ask, “If amyloid beta and tau are so bad, why can’t we just prevent their buildup in the brain?” That’s where the story gets a bit more complicated. So we’ll come back to this later in the book. But be aware that tens of thousands of researchers worldwide are trying to figure out just how amyloid beta and tau work and how to stop them from doing what they do.
The Search for Biomarkers
Biomarkers are indicators of the existence of or the potential for developing a specific disease. The quest for biomarkers is of central interest to biomedical researchers in all fields. A biomarker may be the presence of a certain component in the blood or some other bodily fluid. For atherosclerosis, bad cholesterol is a biomarker—an indicator that the individual with high blood LDL (low-density lipoprotein) is on the pathway to ill health. For prostate cancer, PSA (prostate-specific antigen) is often used as a biomarker. A biomarker can also be a behavioral, psychological or physiological indicator as we will cover later in this volume. By knowing what biomarker is best for determining if a specific disease is present, doctors can then assess the situation, determine the risk and help their patients accordingly.
So what is the biomarker? Actually there is more than one current biomarker for Alzheimer’s disease and others are being searched for even as you read this chapter. In Chapter 11 we’ll talk about this quest for biomarkers. For now, let’s look at the prime candidates. To do this we need to look mainly at two events we’ve already touched upon: the appearance of amyloid plaques and neurofibrillary tangles. Let’s start with the plaques.
As discussed above, we know that amyloid plaques form outside of nerve cells in the brain and are tightly linked to the development and progress of Alzheimer’s disease. Most researchers believe this accumulation of amyloid peptides and other proteins in those plaques is a primary cause of Alzheimer’s disease in the majority of cases. Thus the “amyloid hypothesis” argues that the deposition of amyloid plaques occurs, which leads to problems with nerve cell function, which then lead to the changes in a person’s cognitive abilities. Since the major and consistent component that is present in all amyloid plaques is the short amyloid beta peptide, then it follows that this peptide should be an excellent biomarker for the disease. As a biomarker, the presence or absence of this peptide in the wrong places at the wrong time is evaluated. Thus the loss of amyloid beta peptide from the cerebrospinal fluid is a useful biomarker. This loss occurs as the amyloid beta in the cerebrospinal fluid moves into the brain where it is converted into plaques. Thus another biomarker is the appearance of that amyloid beta in plaques in the brain as detected by PET (Positron Emission Tomography).
Since tau proteins make up the tangles in the Alzheimer’s brain, the presence of tau protein variants is another major biomarker. (There is evidence that neurofibrillary tangles are a later event in the progression of the disease and not a cause.) Another biomarker is evidence of brain atrophy as measured using MRI (Magnetic Resonance Imaging). Yet another is the decrease in a person’s cognitive function—their ability to remember and reason, for example—as revealed by various psychological tests.
It is widely believed that using two or more of the aforementioned biomarkers can serve as an indicator of the future development of Alzheimer’s disease. Two questions still remain: “Are there even better biomarkers that will allow us to determine even earlier stages of Alzheimer’s disease?” and “Are there biomarkers that will indicate when the disease actually starts?” These goals are shared by many doing frontline research.
The Pharmaceutical Landscape
Various pharmaceuticals have been approved worldwide to help with the neurodegenerative effects of Alzheimer’s and other cognitive diseases. As with natural remedies, we need to understand why these drugs have been developed and how they work. Is there potential for a cure with any of them or are they simply a short-term but still potentially valuable stopgap? To understand the value of these drugs and to gain more insight into the cause and progression of Alzheimer’s disease we will need to learn a bit about how brain cells work and how they break down in the diseased brain.
The basic truth is simple: we can’t expect to find a cure for Alzheimer’s disease until we understand why it occurs. We can’t just randomly pull a natural or a synthesized drug out of the air and expect that it will be the wonder drug for Alzheimer’s disease. We also cannot rely on unproven opinions and promotions that are presented on the Internet. Biomedical research needs to be done to understand how the disease starts and progresses and it needs to be done in a logical and sequential way though careful study. This is so results can be statistically analyzed to verify if the specific pharmaceutical actually works. How this is and should be done is detailed in later chapters. As we have seen, there is one prime candidate as a primary cause of Alzheimer’s disease. It is the little peptide amyloid beta that we introduced above. These deposits are believed to alter how brain cells work by changing their cell membranes and their inner workings and may in turn cause the formation of neurofibrillary tangles. Much of today’s research focuses on amyloid beta but it may not be alone in causing the symptoms of Alzheimer’s disease.
The Stage is Set
The Baby Boomer cohort has had a major impact on society’s progress. As more and more of this generation have entered the Alzheimer’s disease -sensitive stage of life, their concern is growing. So too is their will to understand what causes Alzheimer’s and to find a way to slow or stop the progress of the disease, if not prevent it in the first place. In this book, we will examine all of these issues and many more that most people have not even considered. This introductory chapter has set the stage for what follows. With the exception of topics related to care of those with Alzheimer’s
