Chapter 57. Biochemical Case Histories
Robert K. Murray, MD, PhD & Peter L. Gross, MD, MSc, FRCP(C)
Case 2: Alzheimer Disease (AD)
Before studying this case, the reader is advised to consult the material in Chapter 5 on AD.
 Deposition of amyloid peptide (A42) in certain parts of the brain is believed by many neuroscientists to be one major cause of AD. It is thought that this 42-amino-acid peptide, occurring as beta sheets, oligomerizes and is deposited around neurons; the oligomers may be toxic to neurones. Deposition of A42 may be due to excessive formation or decreased removal of the peptide. In certain cases of familial AD, specific genes have been identified (eg, these encoding amyloid precursor protein [APP], presenilins 1 and 2, and apolipoprotein E4), which affect the production or removal of A42.
History and Physical Examination
A 72-year-old woman who lived on her own was found wandering around her neighborhood at 2 A.M. Her husband had died 3 years previously and her one son lived some distance away. The lady was confused and taken to the hospital. The son was notified and came immediately to see his mother. She was not able at the time of admission to give a clear history. The son volunteered that she had been diagnosed by a neurologist as having early AD, but had refused to go into a nursing home. She had home help during the day, and had not previously wandered out of her home. Sometimes a lady friend visited and spent the night at her house. In fact, she had appeared relatively normal prior to the present situation, as her son spoke to her on the phone every day of the week. However, her short-term memory had become worse in recent months, and he had become concerned about her. She was on a medication (donepezil) for AD. Otherwise she had no significant medical history. She was kept in the hospital for a couple of days, during which time her family doctor and the neurologist were consulted.
There is no specific treatment for AD at the present time.  Donepezil and several other drugs that are used in the management of AD inhibit the activity of cholinesterase, an enzyme that hydrolyzes acetylcholine (ACh) to acetate and choline. They are used because some studies had shown lower than normal levels of ACh in specimens of brains from subjects who had died of AD. They appear to produce a modest improvement of brain function and memory in some patients. Memantine, a drug that antagonizes N-methyl-D-aspartate receptors, may cause some slowing of the progression of AD. Symptoms such as depression, agitation, anxiety, and insomnia can be treated by appropriate drugs and antipsychotics may be required if psychosis intervenes.
A possible preventive role of omega-3 fatty acids is under study. However, overall, there is as yet no effective therapy for AD. This patient was kept on donepezil and admitted to a nursing home that specialized in caring for patients with AD. Apart from high-quality basic care, the nursing home offered a variety of programs, including music therapy and exercise programs.
 AD is a progressive neurodegenerative condition in which decline of general cognitive function occurs, usually accompanied by affective and behavioral disturbances.
At least 2 million people in the United States suffer from AD, and its prevalence is likely to increase as more people live longer. Some cases have a familial (genetic) basis, but the great majority (~90%) appears to be sporadic. AD is the most common cause of dementia, which can be defined as a progressive decline in intellectual functions, due to an organic cause, that interferes substantially with an individual's activities. AD places a tremendous burden on families and on the health care system, as, sooner or later, most patients cannot look after themselves.
The usual age at onset is over 65 years, but the disease can have an early onset (eg, in the 40s), particularly in cases where there is a genetic predisposition (see below). Survival ranges from 2 to 20 years. It is estimated that about 40% of people over 85 years of age have variable degrees of AD. Loss of short-term memory is often the first sign. AD usually progresses inexorably, and many patients are eventually completely incapacitated.
The diagnosis is usually one of exclusion. A complete neurologic exam is necessary and also a recognized mental status exam. Other forms of dementia (Lewy body, vascular, etc) must be excluded, as must other organic and psychiatric problems; various lab tests may thus be indicated to do this.  In certain cases an MRI or CT scan may be indicated; these will usually reveal variable degrees of cortical atrophy and enlargement of ventricles if AD is present. Considerable research is underway to develop laboratory tests (eg, on blood or cerebrospinal fluid) that will assist in making the unequivocal diagnosis of AD.
The basic pathologic picture is of a degenerative process characterized by the death and consequent loss of cells in certain areas of the brain (eg, the cortex, hippocampus and certain other sites). Apoptosis (a programmed type of cell death in which various mechanisms, particularly the activities of proteolytic enzyme known as caspases, are activated within a cell leading to rapid cell death, may be involved in the cell death occurring in AD. At the microscopic level, neuritic plaques containing aggregated amyloid peptide (A, a peptide of 42 amino acids, occurring in beta sheets) surrounded by nerve cells containing neurofibrillary tangles (paired helical filaments formed from a hyperphosphorylated form of the microtubule associated protein, tau) are hallmarks. Deposits of A2are frequent in small blood vessels.
Intensive research is under way to determine the cause of AD.  Particular interest has focused on the presence of A42, the major constituent of the plaques found in AD. The term "amyloid" refers to a group of diverse extracellular protein deposits found in many different diseases. Amyloid proteins usually stain blue with iodine, like starch, which accounts for the name (amylo denotes starch). The amyloid cascade hypothesis proposes that deposition of A42 is the cause of the pathologic changes observed in the brains of the victims of AD and that other changes, such as neurofibrillary tangles and vascular alterations, are secondary. A42 is derived from a larger precursor protein named amyloid precursor protein (APP), whose gene is located on chromosome 21 close to the area affected in Down syndrome (trisomy 21). Individuals
with Down syndrome who survive to age 50 often suffer from AD.
As shown in Figure 57–2, APP is a transmembrane protein that can be cleaved by proteases known as secretases. In step 1, APP is cleaved by either -secretase or -secretase to produce small nontoxic products. Then in step 2, cleavage of the -secretase product by -secretase results in either the toxic A42 (containing 42 amino acids) or the nontoxic A40 peptide. Cleavage of the -secretase product by -secretase produces the nontoxic P3 peptide. When split off from its parent protein, A42 forms an insoluble extracellular deposit. Aggregation of A42, produced by its oligomerization and formation of beta sheets, is thought by some to be a key event in causing AD. Recent studies have suggested that impairment of clearance of A42 may be an important part of the problem in AD.
Figure 57–2 Add to 'My Saved Images'
Simplified scheme of the formation of A42. Amyloid precursor protein (APP) is digested by -, -, and -secretases. A key initial step (Step 1) is the digestion by either -secretase or -secretase, producing smaller nontoxic products. Cleavage of the -secretase product by -secretase (Step 2) results in either the toxic A42 (containing 42 amino acids) or the nontoxic A40 peptide. Cleavage of the -secretase product by -secretase produces the nontoxic P3 peptide. Excess production of A42 is a key initiator of cellular damage in Alzheimer disease (AD). Among research efforts on AD have been attempts to develop therapies to reduce accumulation of A42 by inhibiting - or -secretases, promoting -secretase activity or clearing A42 by use specific antibodies. (Reproduced, with permission, from Fauci AS et al [editors,] Harrison's Principles of Internal Medicine, 17th ed, McGraw-Hill, 2008, p. 2542.)
Mutations in certain genes have been found in some patients with AD (familial AD). These mutations often predispose to early onset AD. One of these genes is that encoding APP. Table 57–1 summarizes some aspects of the principal genes so far discovered. In general, the effects of the products of these genes are to enhance deposition of amyloid or to diminish its removal. Precise dissection of their mechanisms of action is underway.
Table 57–1 Some Genes Involved in Familial Types of Alzheimer Disease (AD)1
A second part of the amyloid cascade hypothesis is that A or A-containing fragments are directly or indirectly neurotoxic. There is evidence that exposure of neurons to A can increase their intracellular concentrations of Ca2+. Some protein kinases, including that involved in phosphorylation of tau, are regulated by levels of Ca2+. Thus, the increase of Ca2+ may lead to hyperphosphorylation of tau and formation of the paired helical filaments present in the neurofibrillary tangles. Interference with synaptic function is also probable, perhaps secondary to neuronal damage.
Further research may reveal unexpected developments that alter the validity of the amyloid cascade theory as presented above.
Work on AD has shown the probable importance of an abnormally folded peptide in the causation of this important brain disease. It is hoped that further research on AD may result in drugs that will prevent, arrest, or even reverse AD. For example, it may be possible to develop small molecules that prevent formation or deposition of A42, prevent its aggregation, or accelerate its clearance. In addition, it is possible that specific antibodies to A42 or tau could prevent their putative toxic actions.
 AD is one of the so-called conformational diseases in which abnormally folded proteins play a central role in the causation of a disease.
Other examples of these diseases are cystic fibrosis, alpha1-antitrypsin disease, and the prion diseases.
The study of various neurodegenerative diseases is providing dramatic evidence of the importance of protein structure and function in their causation. For example, abnormal forms of the protein huntingtin play an important role in Huntington disease, abnormalities of -synuclein play a role in some cases of Parkinson disease, and prions have been found to play key roles in the causation of bovine spongiform encephalopathy (BSE) and Creutzfeldt–Jacob disease. The application of genomic and proteomic techniques is also beginning to throw light on the causation of major psychiatric disorders, such as bipolar disease and schizophrenia. The importance of genetic and biochemical approaches in understanding disease processes has never been more clear. A simplified scheme of the causation of AD is shown in Figure 57–3.
A tentative scheme of the possible sequence of events in at least certain cases of AD.