Abstract

Keywords

Alzheimer’s disease

amyloid hypothesis

amyloid plaques

ApoE

bapineuzumab

cholinergic hypothesis

dementia

hypercholesterolemia

hypoperfusion

inflammation

mild cognitive impairment

neuropathology

neurofibrillary tangles

tau hypothesis

Alzheimer’s disease (AD), or Alzheimer disease, is a progressive, neurodegenerative disorder of the brain that mysteriously claims the lives of millions of people. It leaves the affected helpless, the community frightened, and the AD research field frustrated.

Mental deterioration in old age has been recognized and described throughout history. However, it was in 1906 that Dr. Alois Alzheimer defined the severe aspects of this condition, based on the autopsy of one of his patients who had died after years of severe memory problems, confusion, and difficulty understanding questions. He described the presence of dense deposits surrounding the nerve cells and twisted fibers in the nerve cells in the brain. Today, we refer to these dense deposits as plaques, areas of complex proteins that deposit in the AD brain. Those plaques found in the AD brain are generally composed of amyloid, an insoluble, fibrous protein. The twisted fibers that Dr. Alzheimer described, now known as neurofibrillary tangles, are abnormally constructed tau proteins, otherwise meant to stabilize the cell cytoskeleton for normal cellular activities. Together, the presence of these neuropathological features confirms the diagnosis of AD; however, it is not agreed upon if these are the cause of neuronal death leading to AD or a by-product of it.

Clinically, the manifestations of AD are also fairly well defined. AD begins with symptoms of dementia, although not everyone with dementia regresses to AD. These symptoms include difficulty with language, memory, perception, thinking, and judgment, and can deteriorate into a stage termed mild cognitive impairment (MCI). The additional symptoms of MCI include difficulty in solving problems, multitasking, and forgetting recent events or conversations, although, again, not everyone with MCI will develop AD. The early stages of AD occur if these symptoms continue to worsen to the point of getting lost on familiar routes, having language problems, losing interest in previously enjoyed activities, and, finally and most tragically, personality changes and the loss of social skills. As the AD progresses, the symptoms worsen to include hallucinations, unawareness of self, and the inability to be independent, thereby requiring full-time care. This cruel disease is equally troubling to family and friends who agonize over the vacant expression on their loved one’s face and are left to painfully watch life slip away. AD finally claims the victim’s life about 8–10 years after the initial diagnosis, chiefly due to coexisting illnesses such as pneumonia.1

The cause of the death of the neurons in the brain is unknown but several recent discoveries have brought to light additional information regarding the pathological basis for AD. Some of these form the basis for hypotheses on AD, the most prominent and influential of which will be illustrated later.

I will take this opportunity to go into more technical detail concerning the mechanisms of the brain and neurons. I cannot fully describe or explain these nuances here, but if you are not familiar with all the terminology used, rest easy knowing that fully understanding this section is not necessary to appreciate the rest of the text. Also, if you are unfamiliar with some terms or would simply like a refresher, please find a brief technical glossary at the end of this book.

As an additional disclaimer, I don’t intend to present myself as an expert on any of the preceding proposed AD mechanisms. While the information I present is accurate, I apologize in advance to specialists in the field for any egregious oversimplifications or omissions made for the sake of conciseness.

Neurological factors

While it has been known since Dr. Alzheimer’s finding in 1906 that amyloid plaques and abnormally constructed tau protein fibers are neuropathological features in the AD brain, only relatively recently has the scientific community begun to learn more about additional factors underlying neuronal death in the disease.

One of the first major discoveries in the 1970s was that of a deficit in choline acetyltransferase, an enzyme that synthesizes the neural transmitter acetylcholine, in the neocortex of the AD brain. Additional studies reported reduced choline uptake, increased acetylcholine release, and the degeneration of cholinergic neurons (those that use acetylcholine as a neurotransmitter) in the specific areas in the AD brain.2–7 These data make up the foundation of the cholinergic hypothesis that the loss of cholinergic neurons, and thus the loss of cholinergic neurotransmission in critical brain areas, contributes significantly to the deterioration in cognitive function of AD patients.8 The contemporary discovery of acetylcholine’s pivotal role in learning and memory further supported this hypothesis.9 Today, the cholinergic hypothesis is the basis of most of the currently available drug therapies to treat AD, which are meant to inhibit cholinesterase, another enzyme that breaks down acetylcholine. As of today, these therapies have had minimal success.10

Another prominent discovery in the 1980s involved neuroinflammation as the cause of neuronal death in the AD brain. In fact, the discovery of a wide array of immune-related antigens in the AD brain helped establish the concept of a specialized immunodefense system in the central nervous system. In particular, as a result of some factors in the AD brain (these are not universally agreed upon), microglia are reactive, setting off a chain of events releasing immune-related antigens including proinflammatory cytokines and chemokines.11 According to the inflammation hypothesis, the increased secretion of these substances, which are potentially neurotoxic, eventually destroys neurons, leading to the development of AD symptoms.12 Some proponents of the inflammation hypothesis also suggest that this sequence triggers the distortion of tau via phosphorylation.12 Overall, the role of inflammation in AD is still widely debated. However, clinical trials targeting inflammation have not been impressive.13

While it is clear that phosphorylated tau (Dr. Alzheimer’s twisted fibers) is somehow involved in the pathogenesis of AD, as either a cause or effect, its exact role is still heavily debated. Many researchers in the field believe that genetic mutations that alter the function and isoform expression of tau, a stabilizing neuronal filament, may initiate a far-reaching transformation that sets off AD. In this model of the tau hypothesis, it is reported that uncontrolled excessive or abnormal hyperphosphorylation of tau results in the transformation of normal adult tau.14 This distorted adult tau begins to pair with other threads of tau to eventually form paired helical filaments, creating neurofibrillary tangles inside neurons. This has disastrous consequences, beginning with the collapse of the internal neuronal transport system and ending with cell death.15–17 It was suggested that this may be the first malfunction in biochemical communication between neurons and later in the death of the cells.18 It was reported that such impaired microtubule assembly due to the hyperphosphorylation of tau was found in AD brain extracts.19 Subsequent research over the past 20 years has studied tau phosphorylation and function, and how site-specific phosphorylation modulates the physiological and pathological roles of tau. However, targeting hyperphosphorylated tau is difficult since it is inside neurons. One potential treatment is to administer modified methylene blue, which seems to prevent tau from aggregating to form those tangles.20 This treatment showed enough promise in one Phase 2 trial to proceed to Phase 3 clinical trials with a related derivative. Other related trials are underway for drugs that stop phosphorylation of tau and antibodies against tau.21

Non-neurological factors

Besides discoveries regarding the neuropathology of AD, the AD field has also uncovered non-neurological risk factors and associated features of AD.

Perhaps the most straightforward discovery is the connection of vascular risk factors to the development of AD. In fact, the vascular hypothesis suggests that the pathology of AD begins with hypoperfusion, a decreased blood flow to the brain. Support for a vascular cause of AD comes from epidemiological, neuroimaging, pathological, and clinical studies.22 The hypothesis considers...