Chapter 65. Dementia Including Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder projected to afflict more than 13 million Americans and 81 million individuals worldwide in the next 40 to 50 years. The disease is characterized by progressive cognitive and behavioral deficits accompanied by diffuse structural abnormalities in the brain. AD is associated with significant morbidity and mortality and is currently among the 10 most common causes of death in the United States. Unfortunately, the devastations of AD affect both the patient and caregivers, and involve numerous aspects of human life including physical, socioeconomic, psychological, functional, and quality of life. In addition, caring for patients with AD places heavy financial burden on patients, families, and the health care system at large. In the United States, the average annual cost of managing a patient with AD varies between $18,400 and $36,000, while, as a nation, we spend close to $100 billion each year to care for patients with AD. Similar data are reported from other countries as well. In the United Kingdom, more than $8 billion or 0.6% of the gross domestic product is spent each year to care for patients with cognitive impairments. Recognizing the enormity of the burden of AD, international collaborations between clinicians, researchers, policy makers, patient advocacy groups, the media, and many others have increased public awareness of the global impact of the disease and have laid the foundation for the development of effective preventive and therapeutic strategies as well as improvements in care management for patients with AD.

Recent advances in biomedical research have provided critical knowledge related to the pathobiology of AD and mechanisms underlying neuronal plasticity and death. While current therapies work mainly to slow the inevitable progression of the disease, these newly identified mechanisms now serve as targets to develop effective novel therapies that could either delay or preferably arrest the progression of AD. Moreover, treatment strategies are being developed for primary prevention of AD, especially for individuals at increased risk for the disease. The present chapter includes information on the major aspects of AD, including the pathology, epidemiology, clinical presentations, diagnosis, management, and potential neuroprotective therapies. Details related to non-Alzheimer types of dementia are discussed in Chapter 67.

Alzheimer's disease is characterized by progressive cognitive and behavioral deficits accompanied by diffuse structural abnormalities in the brain. The common symptoms of the disease include memory loss, confusion, impaired judgment, personality changes, disorientation, and loss of language skills. Based on the onset of symptoms, AD is normally divided into two groups: early- (<60 years) and late-onset (>60 years). Early-onset, also called familial AD (FAD), accounts for approximately 3% of all the cases and has to date been linked to mutations in the genes for the amyloid precursor protein (APP; gene name APP) on chromosome 21, presenilin 1 (PS1; gene name PSEN1) on chromosome 14, and presenilin 2 (PS2; gene name PSEN2) on chromosome 1. Among these genes, more than 160 different mutations have so far been identified, accounting for approximately 40% of all cases of FAD. Most of the mutations (∼140) are found in the PSEN1 gene, while the remaining are almost equally split between APP and PSEN2. FAD is characterized by early onset (from mid 30s to mid 50s) of cognitive symptoms, but is clinically indistinguishable from late-onset AD.

Late-onset AD (LOAD), also called sporadic AD, accounts for close to 97% of all cases of AD and to date has not been linked with any mutations. Aging is the single most important risk factor for LOAD. Additionally, LOAD has been associated with many other environmental and genetic risk factors, including hypercholesterolemia and other vascular risk factors, history of head trauma, and low educational attainment. Among the genetic risk factors, the ϵ4 allele of the apolipoprotein E (APOE) gene on chromosome 19 is the only polymorphism consistently found associated with LOAD in both case–control and genetic studies. The APOE gene exists as three major alleles (ϵ2, ϵ3, and ϵ4) that encode three different ApoE isoforms: ApoE2, ApoE3, and ApoE4. Interestingly, these isoforms only differ in amino acid sequences either at position 112 and/or 158: E2 (cysteine 112, cysteine 158), E3 (cysteine 112, arginine 158), and E4 (arginine 112, arginine 158). The inheritance of the ϵ4 allele confers a major risk for developing AD, while the ϵ2 allele confers protection. For example, presence of one copy of the ϵ4 allele increases risk of AD by fourfold, whereas inheritance of two copies enhances the risk by almost ninefold. However, unlike genetic mutations associated with FAD, the presence of APOE4 (or other polymorphisms) is neither necessary nor sufficient to cause AD. Even though the first report of an association between APOE4 and AD was published over a decade ago, the precise molecular mechanism(s) underlying this association still remain elusive. It is currently unknown if the APOE4 allele influences the rate of production, clearance, or aggregation of amyloid β-peptide or whether it influences cholesterol metabolism and inflammation that reportedly play a major role in the pathobiology of AD.

In addition to APOE4, more than 40 other polymorphisms have been associated with increased risk for LOAD. However, none of these associations has been uniformly confirmed in every population-group studied to date.

The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, and amyloid angiopathy accompanied by diffuse loss of neurons and synapses in the neocortex, hippocampus, and other subcortical regions of the brain (Figure 65-1). The predominance of the amyloid plaques versus neurofibrillary tangles or amyloid angiopathy can differ from one patient to another. However, the neuronal/synaptic loss is a constant feature and eventually the direct cause of dementia. Interestingly, the distribution of the disease pathology seems to follow a region-specific pattern with the amyloid plaques more prevalent in the neocortex and the neuronal/synaptic loss more prevalent in the hippocampus, posterior cingulate, and corpus callosum areas of the brain closely involved with memory formation and higher cortical activities. The amyloid angiopathy is often observed in the “classical” LOAD, but seems to be more prevalent in a small subgroup of FAD (Dutch E693Q and Iowa D694N mutations in the APP gene). Finally, AD brains are also characterized by a diffuse and widespread invasion of reactive astrocytes, mostly concentrated in the hippocampus and around areas of neuronal loss; however, this is not specific to AD and can be observed in other neurodegenerative disorders associated with inflammatory and neurotoxic insults.

The dominant component of the plaque core is amyloid β-peptide (Aβ) organized in fibrils of approximately 7 to 10 nm intermixed with nonfibrillar forms of the peptide (Figure 65-1). The most characteristic form of the amyloid plaque, the “neuritic plaque”, is characterized by a dense core of aggregated fibrillar Aβ, surrounded by dystrophic dendrites and axons, activated microglia, and reactive astrocytes. In addition, diffuse deposits of Aβ, likely representing a prefibrillary form of the aggregated peptide, are found without any surrounding dystrophic neurites, astrocytes, or microglia. These diffuse plaques can be found in limbic and association cortices, as well as in the cerebellum.

The other neuropathological hallmark of AD is a neurofibrillary tangle (NFT) found exclusively in the cytoplasm of neurons (Figure 65-1). The tangles appear as paired, helically twisted protein filaments composed of highly stable polymers of cytoplasmic proteins called tau. Tau comprises a group of alternatively spliced proteins found in the cytoplasm that possess either three or four microtubule-binding domains and can assemble with tubulin, thus helping the formation of cross bridges between adjacent microtubules. Tau proteins can be phosphorylated in multiple sites and the degree of phosphorylation is inversely correlated with binding to microtubules. As a result, highly phosphorylated tau proteins dissociate from microtubules and polymerize into filaments forming NFTs. In addition to AD, the abnormal accumulation of filamentous tau is observed in frontotemporal forms of dementia, progressive supranuclear palsy, corticobasal degeneration, and Pick disease. Contrary to prior belief, tau proteins themselves can cause dementia, and multiple mutations in the tau gene have been found in frontotemporal dementia with parkinsonism. The possible role of tau proteins in the pathogenesis of AD and their potential interaction with Aβ are still unclear and are discussed in the next section.

Amyloid Precursor Protein Processing and Generation of aβ

Aβ is a 39 to 43 amino acid hydrophobic peptide proteolytically released from a much larger precursor, the amyloid precursor protein (APP). The generation of Aβ from APP (Figure 65-2) requires the sequential recruitment of two enzymatic activities: β-secretase, also called BACE1 (beta-site APP cleaving enzyme 1), and γ-secretase, a multimeric protein complex containing presenilin, nicastrin, Aph-1, Pen-2, and CD147. The β cleavage is the rate-limiting step and occurs before the γ cleavage. It liberates a large N-terminal fragment of the protein (sβAPP) that is released in the extracellular milieu and a small (∼12 kDa) membrane-anchored fragment called β-APP-CTF (or C99). The release of the large N-terminal domain allows subsequent γ cleavage, and liberation of Aβ and the signaling of active intracellular domain of APP (Figure 65-2). Generation of Aβ40 and Aβ42 results from γ cleavage of Aβ at positions 40 and 42, respectively. The release of Aβ in the extracellular milieu is followed by oligomerization and aggregation in the form of fibrils and amyloid plaques. Additionally, small Aβ aggregates are also found in the soma of the neurons suggesting that the Aβ fragments can escape secretion and aggregate in the intracellular environment.

The molecular mechanisms underlying the toxicity of Aβ are still being investigated and currently incompletely understood. However, recent research seems to indicate that small Aβ aggregates (oligomers), which represent the “preplaque” neurotoxic species of Aβ, act as the proximate cause of neuronal injury and synaptic loss associated with AD. Additionally, the C-terminal tail of APP can undergo further processing at amino acid 664 of APP695 liberating two small cytosolic fragments, Jcasp (from aa. 649 to 664 of APP695) and C31 (containing the last 31 amino acids of the C-terminus of APP, from aa. 665 to 695). Both these fragments are generated only after γ cleavage, require caspase-mediated processing of APP, and can activate proapoptotic pathways in a variety of cellular systems.

It is widely known that, although the major source of Aβ, APP exerts several important functions in the nervous system. APP comprises a group of ubiquitously expressed proteins that are generated from one single gene by differential splicing, resulting in three major isoforms of 695, 751, and 770 residues. The first isoform (APP695) is highly abundant in neurons and differs from the others in the absence of a 56-amino-acid domain that is homologous to the Kunitz-type of serine protease inhibitors. Among others, some of the important proposed normal functions of APP include serving as a cell-surface receptor, growth factor, protease inhibitor, cell–cell interaction molecule, coreceptor/partner in the endocytic/lysosomal network, coagulation inhibitor factor, cell-surface scaffold protein, kinesin-interacting molecule for axonal transport, and transcription factor.

Aβ: Pivotal Role in the Pathogenesis of Alzheimer's Disease

The most critical clinical link between Aβ and AD came from the observation that patients with Downs' syndrome (trisomy 21) had a higher propensity of developing a clinical and pathological phenotype resembling AD, thereby suggesting a potential association between AD and chromosome 21. This observation was further strengthened by the fact that Aβ was the major component in plaques from both patients with Downs' syndrome and AD, and that its genesis was related to a gene (APP) located on chromosome 21, close to the obligate Downs' syndrome region. Following the identification of APP, several groups found mutations in the APP gene that were linked to familial forms of AD. Given that the duplication of the APP locus could result in early AD and that Downs' syndrome patients with partial trisomy 21 developed AD only when the trisomy was proximal to the APP locus, the potential direct relationship between APP metabolism and AD seems strong. Furthermore, causative mutations in the genes that encode for presenilin 1 (PS1) and presenilin 2 (PS2), which are also implicated in the metabolism of APP, have been found and are associated with familial forms of AD, thereby conferring additional strength to the linkage between APP/Aβ metabolism and AD.

Although the generation of Aβ from APP seems to be a pivotal step in the pathobiology of AD, it does not explain all the neuropathological changes observed in patients with AD. For example, examination of the brain of transgenic mice expressing human APP harboring one or more FAD-associated mutations reveals presence of amyloid plaques and some synaptic loss and cognitive deficits, but absence of tau pathology and astrocytosis. This suggests that additional biochemical/molecular events are required to develop the full pathological spectrum of AD. To circumvent this issue, several new animal models have been generated where human APP is accompanied by additional genes. These genes include the presenilins (harboring FAD-associated mutations), tau, and ApoE. Recently, several transgenic mice models harboring three or five FAD-associated mutations (respectively called 3X and 5X mice) in two or more genes have been generated. All of these models demonstrated that Aβ is an essential element for the development of AD-like neuropathology and revealed a close relationship between Aβ and the phosphorylation/aggregation state of tau. However, none of the mouse models fully reproduce the classical AD-phenotype; thereby again suggesting that Aβ seems to be necessary but not sufficient to produce the entire spectrum of AD neuropathology.

Transgenic mice expressing the human microtubule-associated protein tau develop the typical tau-related pathology found in individuals suffering from frontotemporal dementia with parkinsonism; however, they do not develop amyloid plaques suggesting that tau is not required for the formation of plaques. Crossing these mice with APP transgenic mice potentiates tau-related pathology and neuronal loss but does not aggravate plaque pathology suggesting that Aβ acts upstream of tau in the classical AD-phenotype. However, studies from patients with AD, mouse models, and ex vivo cellular systems indicate that Aβ and tau can interact synergistically, thereby fostering their respective aggregation and neuronal loss. The true relationship between Aβ and tau is more complex than previously thought and likely involves additional molecular and biochemical pathways acting upstream of both Aβ and tau in the AD brain.

The recent identification of the gene that encodes BACE1, the rate-limiting enzyme in the biosynthesis of Aβ, prompted the generation of “knock-out” mice that lack BACE1. Crossing these mice with the APP mutant mice models revealed that elimination of β cleavage of APP is sufficient to resolve many aspects of AD pathology, including the synaptic impairment and cognitive phenotype of the animals. Moreover, these approaches indicated that BACE1 represents a viable target for development of effective treatment strategies for AD, given that disruption of BACE1 does not result in a strong phenotype in the mouse. Overall, there is extensive evidence from laboratory research that Aβ plays a major role in the pathogenesis of AD; however, there are likely additional, yet unidentified, molecular pathways that contribute to the overall pathobiology of AD.

Alzheimer's disease is the most common cause of dementia in older adults, currently affecting more than five million Americans and more than 24 million individuals around the world. Unless effective preventive strategies are identified, it is anticipated that the prevalence of AD will double every 20 years. Of note, the United Nations predicts that the major rate of increase in the prevalence of AD will likely occur in developing countries like India and China that may not possess all the essential resources, public health support system, or medical expertise to care for patients with AD.

There is clear evidence that a number of risk factors significantly enhance the overall risk for developing AD. These risk factors relate to both genetic and nongenetic markers, and are discussed below.

Aging

Aging is the single most important and validated risk factor for AD. The projected increase in AD prevalence in the coming decades is in part related to recent increases in the average human life span. Almost all of the epidemiological studies indicate that the incidence of AD increases with aging. For example, in the year 2000, the age-specific distribution of patients with AD was 5% between the ages of 65 and 74 years, 18% between the ages of 75 and 84 years, and 45% above the age of 85 years. Additionally, age-associated increases in the amount of amyloid plaques and NFTs in the brains of older persons further underscore a strong relationship between aging and AD pathology. Although not clearly understood, converging findings from recent research provides some clues concerning the potential molecular pathway(s) underlying the association between aging and AD. This pathway acts downstream of the insulin-like growth factor 1 receptor (IGF1-R) and plays a major role in determining both the lifespan and age-associated diseases. In general, activation of IGF1-R signaling accelerates aging and shortens lifespan, while a partial block—as achieved with either genetic or biochemical approaches—delays aging, extends lifespan, and, most importantly, delays the progression of many age-associated diseases, including AD and type 2 diabetes mellitus. Recent biochemical and genetic studies have delineated a precise molecular pathway involving IGF1-R, neurotrophin signaling, BACE1, and APP metabolism, suggesting that pharmacological approaches aimed at IGF1-R signaling might help delay the progression as well as onset of AD.

Aging and IGF1-R signaling are both associated with cerebrovascular dysfunction, which, emerging evidence supports, may play a key role in the development of AD. An increased exposure time to age-dependent vascular risk factors or an interaction between aging and vascular risk factors may in part account for the effects of aging on the pathobiology of AD. Thus, targeting treatment of vascular risk factors may ameliorate some of the age-associated risk for AD.

APOE Genotype

Late-onset AD is the most common form of the disorder, accounting for more than 90% of all AD cases. Although early-onset AD has strong genetic links, many cases of LOAD are seen in individuals without any clear genetic predisposition. A common polymorphism in the apolipoprotein E (APOE) gene is the major determinant of risk in families with LOAD. Of the three common allelic forms (APOE2, APOE3, and APOE4), APOE4 is associated with up to fourfold increased risk of developing AD among individuals with at least one APOE4 allele. However, APOE4 genotype is neither necessary nor sufficient for the development of AD. APOE4 allele may contribute to AD by influencing processes related to the development of AD, including altering the rate of production, clearance, or aggregation of amyloid β-peptide and/or influencing cerebral cholesterol metabolism and inflammation. Currently, routine genetic testing for LOAD is not recommended. Recent estimates based on twin studies suggest that nearly 50% of LOAD cases may be related to APOE allele and other unidentified genetic factors.

Gender

Although controversial, there is some evidence that AD is more common among women. Specifically in the population-based studies published to date, more than half reported a greater risk of AD in women, while the others found no difference. It is generally believed that the discrepant findings between various studies are likely owing to several important reasons, including methodological differences and a failure to account for the potential gender-related variability in education, occupation, and lifestyle variables that can directly affect the risk of AD. Some data support that estrogen deficiency following menopause may contribute to the development of AD; however, the effects of estrogen replacement therapy on cognition remains controversial.

Hypercholesterolemia and Vascular Risk Factors

There is mounting evidence that midlife vascular risk factors are associated with an increased risk of AD in later life. In epidemiological studies, hypercholesterolemia, hypertension, hyperhomocysteinemia, obesity, diabetes mellitus, and elevated inflammatory markers have all been associated with enhanced risk of developing AD. Furthermore, APOE4 allele is related to abnormal cholesterol metabolism suggesting that the increased risk for AD associated with this genotype may be partially mediated through dysregulation of cholesterol. The cholesterol–AD connection is further supported by results from animal studies showing that hypercholesterolemia stimulates the amyloidogenic pathway of APP leading to increased production and deposition of Aβ. Conversely, decreased levels of cholesterol produce the opposite effect reducing the production and deposition of Aβ. Not only do some vascular risk factors appear to influence Aβ metabolism, but conversely, soluble Aβ has been shown to induce dysfunction in cerebral vessels of rats and in cultured endothelial cells. As both Aβ deposition and cerebrovascular dysregulation are two early findings in preclinical AD pathology, these processes most likely work synergistically to accelerate neuronal degeneration. Although the evidence supporting an association between vascular disease and AD is increasing, it is presently unclear whether treating these modifiable vascular risk factors will affect the development or progression of AD. Clinical trials are currently underway to evaluate the potential role of treating these risk factors in preventing or delaying AD progression.

The fact that cerebrovascular diseases such as vascular dementia and cerebral amyloid angiopathy (CAA) share common risk factors with AD supports that their pathologic mechanisms are related. A clear separation between vascular forms of dementia and classical AD based on cognitive impairment is extremely difficult. Typical patients with vascular dementia have a history of vascular disease and show a more pronounced impairment in executive function with only mild memory deficits. The presence of white matter hyperintensities and lacunar infarcts demonstrated by MRI constitutes an important criterion to support the diagnosis of vascular dementia. However, only 2% to 3% of patients with dementia fulfill the diagnostic criteria of pure vascular dementia. In contrast, a large group of patients show an overlapping phenotype with subcortical white matter changes, hypoperfusion, microinfarcts, and amyloid angiopathy. These patients tend to progress into classical AD and will show some degree of amyloid plaques and tau aggregates at autopsy, together with microglia and astrocytic proliferation. CAA is characterized by abnormal accumulation of fibrillar Aβ (especially Aβ40) in the walls of meningeal and cortical arterioles, venules, and capillaries. The damaged vessels undergo spontaneous rupture, and the patients often present with subcortical white matter changes and microhemorrhages. An autosomal dominant form of CAA is caused by a point mutation in the APP gene (Dutch-type) and is a form of FAD. Understanding the overlapping pathologic mechanisms among AD, vascular dementia, and CAA may help to identify common targets for disease-modifying therapies.

Head Trauma

Several epidemiological studies have indicated that a history of severe or repeated head trauma is a risk factor for cognitive decline and AD. The majority of patients develop AD, although a minority might manifest dementia of Parkinson disease and depression. Neuropathological examination of the brain from patients with a history of head trauma generally reveals changes of diffuse amyloid plaques together with tau pathology, inflammatory response, and loss of cholinergic neurons. A smaller number of patients show diffuse α-synuclein reactivity, Lewy body–type aggregates, and loss of dopaminergic neurons resembling Parkinson disease. In animals, pathological changes following experimental head trauma reveal transient upregulation of BACE1 together with increased generation of Aβ. These features are accompanied by tau hyperphosphorylation and increased caspase-mediated cleavage of APP. Thus, head trauma may lead to AD by triggering accelerated neurodegeneration.

Depression

Depression is a common psychiatric condition in the elderly and widely reported to present with symptoms of cognitive and functional impairment, commonly grouped into the clinical entity of pseudodementia. Furthermore, more than 30% of patients with AD develop depression during the course of their illness, and might present with the symptoms of depression as the first clinical manifestation of underlying AD. Thus, a better understanding of the potential relationship between depression and AD is of pivotal clinical significance. Although not confirmed universally, there is converging evidence from several studies that a history of depression can increase the risk of AD later in life. Findings of a recent meta-analysis and metaregression analysis involving 20 retrospective and prospective studies supported an increased risk of AD in patients with prior history of depression. The pooled odds ratio for developing AD in this analysis was 2.03 for case–control and 1.90 for cohort studies. To date, the precise mechanism(s) underlying the association between depression and enhanced risk for AD is unknown. However, several potential mechanisms have been proposed, including elevated levels of cytokines observed in both patients with AD and depression, increased association of vascular risk factors with the pathobiology of AD as well as depression, and the potential role of APOE4 allele in enhanced risk for both AD and depression. Clearly, more research is necessary to better understand the biological basis of increased risk of AD in patients with a history of depression.

Education and Ethnicity

There is some evidence, albeit controversial, from epidemiological studies that higher education may protect against the development of AD. Individuals with elementary level education might be at an increased risk of developing AD, compared to those with high school and college education. Of note, these findings have not been substantiated by all studies and need to be systematically evaluated in larger epidemiological studies. The exact mechanism underlying the neuroprotective effects of higher education is currently unknown; however, based on the “use it or lose it” theory there is suggestion that individuals with higher education might have more neurons to lose before they cross the threshold of developing dementia.

It is generally presumed that AD affects all ethnic groups equally. However, there is some recent evidence that the disease might be more prevalent in certain ethnic groups. In a population based study in the Washington Heights and Inwood communities of New York City, the cumulative incidence of AD was increased twofold among individuals of African-American and Caribbean Hispanic origin. This ethnicity-based incidence of AD did not change following corrections for differences in the number of years of education, or a history of diseases like hypertension, diabetes mellitus, and cardiovascular disease. Although not universally confirmed, other studies also support these findings. In a study in Houston, both the incidence and prevalence of AD were higher among African-Americans and Hispanics than retirees of Caucasian origin. Although speculative, it is possible that the increased risk of AD among the above ethnic groups may be because of a higher incidence of comorbid vascular and cardiovascular diseases and a higher prevalence of APOE4 genotype.

The most common symptoms of AD include cognitive deficits and functional impairments. These deficits progress over time and eventually result in loss of activities of daily living, frequently necessitating admission to nursing homes and leading to eventual death. The majority of patients with AD initially present with slowly progressive memory impairments; however, in up to 40% patients the initial presentation might involve nonmemory symptoms like language impairments, symptoms of depression, personality changes, extrapyramidal manifestations, and visuospatial deficits. These patients are very likely to be misdiagnosed and require comprehensive evaluation by a physician with special expertise in dementia.

Typical Clinical Presentation of AD

Slowly progressive memory loss for recent events is the most common clinical presentation of AD. Patients with AD frequently have problems remembering recent conversations, dates, appointments, and may misplace items at home. Many patients are not aware of these deficits and are brought to medical attention by their family members or friends. The memory deficits of AD are generally differentiated from those caused by normal aging by the fact that these deficits are progressive and interfere with daily living activities. Cognitive changes associated with healthy aging, although frustrating, are caused by age-associated decline in mental processing speed and difficulty learning new material. However, these changes are not associated with alterations in day-to-day function. Memory loss leading to a change in functional status is not a part of normal aging and warrants further evaluation.

The second most common clinical presentation of AD is impairment in language function. Seen in up to 40% to 50% patients, these impairments generally start with word-finding problems followed by paraphasic errors and circumlocution. These initial deficits lead to expressive aphasia accompanied later with receptive and global aphasia. Unfortunately, given the impairments in communication, patients with AD having significant language impairments generally progress rapidly and have a poor prognosis.

Impairments in executive function are common early deficits in AD, leading to poor judgment, organization, reasoning and abstract thinking, and resulting in inability to complete complex demanding tasks. Deficits in concentration and attention are other common symptoms seen in patients with AD. These impairments lead to tangential tendencies, disorientation, and an inability to successfully complete daily tasks. Persons exhibiting deficits in visuospatial abilities may have problems with driving, dressing, using eating utensils, and walking.

As the disease progresses, changes in personality are commonly seen in patients with AD and may include increased passivity, lack of interest, restlessness, and overactivity. More than 30% of persons with AD develop symptoms of depression, which may be the first clinical presentation of the disease. Early signs of depression in patients with AD include changes in behavior, loss of appetite, alterations in sleep, social withdrawal, and a decline in physical function. Sundowning, or worsening of behavior and cognitive symptoms in the evening, is also common in patients with AD and may be because of changes in circadian rhythm from loss of sunlight.

In the later stages of the disease, individuals may have increased confusion, dysphagia, poor gait, and repeated falls. In some patients with AD, disruptive behaviors may increase with aggression, agitation, and physical or verbal hostility; in others, these behavioral symptoms lessen with disease progression. The majority of patients become increasingly frail and dependent for self-care and activities of daily living with many patients developing bowel and bladder incontinence. Persons in the late stages of AD may become immobile and bed-bound, which increases their risk of developing pressure sores, malnutrition, and dehydration. The most common causes of death in patients with AD include pneumonia, urinary sepsis, dehydration, pressure sores, fractures, and malnutrition. The median survival period from the time of diagnosis to death generally varies between 8 and 10 years, although some patients, especially those with FAD, die earlier.

Atypical Clinical Presentations of Alzheimer's Disease

It is widely reported that between 20% and 40% of patients with AD will initially present with atypical features of the disease. Unfortunately, these patients are commonly misdiagnosed with either a personality or related disorder, and may need to be evaluated by a specialist. As noted earlier, one of the common atypical presentations of AD is impairment in language. These patients are frequently misdiagnosed as having suffered a stroke. The other atypical presentation of AD includes prominent extrapyramidal manifestations. Between 5% and 10% of patients with AD might initially present with features resembling Parkinson disease, consisting of mild rigidity of extremities, hypokinesia, and expressionless face. However, these patients generally do not present with the classical Parkinsonian tremors and do not respond well to dopaminergic drugs. Another atypical feature of AD, seen in approximately 10% patients with AD, includes symptoms of behavioral disinhibition. These patients may make socially unacceptable remarks, become increasingly difficult to live or work with, and may be misdiagnosed with a personality disorder. Finally, less than 5% patients with AD present with symptoms of Balint syndrome, consisting of visual agnosia and ataxia, and complaints of inability to see.

Overall, it is important to recognize that AD can present itself with varied clinical features, and while memory impairment is a critical component of the disease, it is not the only clinical manifestation. Atypical clinical presentations of AD are common and should be evaluated by a physician with special expertise in dementia. Clearly, a misdiagnosis of AD has major serious adverse consequences including emotional, occupational, social, and financial.

Diagnosis of AD involves a comprehensive medical, psychiatric, and neurological evaluation of a patient with cognitive impairment. To date, there is no clinical, laboratory, genetic, or neuroimaging investigation that can definitively diagnose AD. Thus, the diagnosis of AD is largely based on clinical evaluation. In specialized centers, there is up to 10% to 15% chance that the diagnosis of AD could be incorrect; in a general practice environment, an incorrect diagnosis may be made in approximately 30% to 40% of cases, especially if the initial presentation of disease is atypical. Definitive diagnosis of AD can only be made on neuropathological examination of the brain following death.

While the differential diagnoses for AD are extensive (Table 65-1), in usual practice making a clinical diagnosis of AD involves differentiating whether a patient's memory complaint is related to normal aging, mild cognitive impairment (MCI), delirium, depression, or a true dementia such as AD. Differentiating between these various conditions is critical for identifying whether or not the memory complaint is part of a progressive neurodegenerative disorder and for choosing appropriate treatment strategies. An algorithm for approaching the patient with memory complaints is shown in Figure 65-3, integrating various established diagnostic criteria.

While a decline in mental processing speed and difficulty learning new material may be seen with normal aging, MCI is considered to be a predementia condition. Seen in up to 15% to 20% of older adults, MCI was originally characterized as a stage of memory impairment beyond normal aging in which other cognitive domains were preserved and daily function remained intact. Original criteria for MCI are outlined in Table 65-2. Findings from several epidemiological studies have indicated that between 12% and 15% of persons each year with MCI will progress to AD or other forms of dementia. MCI criteria have now been expanded to include both patients with memory impairment (amnestic MCI, with single vs. multiple cognitive domains affected) and those in whom memory function is intact, but other cognitive domains are impaired (nonamnestic MCI, single vs. multiple domain). Persons with amnestic MCI are more likely to progress to AD, whereas those with nonamnestic MCI may be more likely to progress to other forms of dementia, such as frontotemporal dementia, dementia with Lewy bodies, or vascular dementia. A history of intact functional status is a critical distinguishing feature between MCI and early AD and requires careful history-taking and collaborative history from family and/or friends.

Delirium is associated with an acute or subacute onset of fluctuating cognitive dysfunction and can be caused by a wide variety of medical conditions and medications. In patients with delirium, a careful history frequently can tease out the temporal relationship between the onset of potentially reversible cognitive symptoms and contributing underlying medical problems or medications. Depression may cause “pseudodementia” by leading to impaired concentration and attention, thus, affecting an individual's ability to attend to tasks on cognitive testing. Dementia is differentiated from the above-mentioned conditions in that it is a progressive, irreversible process that causes impairment in two or more cognitive domains (such as memory, language, and executive functioning) to the degree that it impairs social or occupational performance. Such changes in cognitive function cannot be attributed to delirium or depression. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for dementia are listed in Table 65-3. Once a diagnosis of dementia is suspected, the clinician must differentiate between various causes of dementia, discern if it is multifactorial, and decide if there is any reversible component to the cognitive loss that can be addressed.

AD is the most common form of dementia in the United States, accounting for 50% to 90% of all dementia cases. Dementia with Lewy bodies, vascular dementia, and frontotemporal dementia are other common forms of dementia (Table 65-4). Details of the clinical and pathological features of these dementias are covered in Chapter 67. Differentiating AD from other causes of memory loss can help clinicians choose effective therapies, anticipate behavior changes and other potential complications, and provide patients and caregivers information on prognosis. AD is characterized by a gradually progressive decline in memory and other cognitive abilities to the degree that it impairs social or occupational performance. These cognitive deficits must represent a decline from a previous level of functioning. The diagnosis of AD is a clinical diagnosis, with the only “gold standard” being autopsy confirmation. The most widely used diagnostic criteria for the disorder include DSM-IV criteria and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorder Association (NINCDS-ADRDA) criteria (Tables 65-5 and 65-6).

In many cases, a clinical diagnosis of AD can be made in a primary care office setting using a careful history, a focused physical examination, cognitive screening tools, and appropriate laboratory data (Figure 65-3 and Table 65-7). A careful history should include collaborative information from the patient, family, caregivers, and/or friends. A patient's baseline level of functioning may be estimated based on educational background as well as occupational history, including detailed information on the highest level tasks associated with each vocation. In persons who have not worked outside the home or who are retired, questions on hobbies, household management, and other volunteer activities will provide important information on the patient's previous level of functioning. Changes in the person's ability to carry out these tasks should then be ascertained, and the degree to which these impairments affect daily functioning should be documented. Questions about changes in daily functional activities will help the clinician isolate problem areas representing functional decline.

Ascertaining the time course over which the memory symptoms developed is important, as AD is characterized by a gradually progressive decline in cognitive function occurring over years. Frequently, an inciting event that disrupts coping skills, such as a hospitalization or the death of a spouse, will draw the attention of family members to a person's memory problems. The family may give a history of an acute onset of memory impairment following the inciting event, but careful questioning may identify memory problems preceding that time period and point to a gradually progressive course.

Additional information on safety should be obtained, including inquiries on medication management, kitchen fires, driving, wandering, financial scams, use of power tools, and hunting or other use of firearms. A review of systems should include questions on depression, tremors, rigidity, falls, dysphagia, urinary incontinence, stroke or transient ischemic attack symptoms, waxing and waning level of consciousness, and visual hallucinations.

A past medical history of cardiovascular disease and associated risk factors, coronary artery bypass surgery, head injury, seizures, depression, Parkinson disease, and heavy alcohol use may help guide the clinician in making a diagnosis. A careful substance use and medication history should be obtained, including specific questions regarding use of alcohol and common over-the-counter anticholinergic medications that can worsen memory, such as antihistamines.

The physical examination should include assessment of general appearance, such as level of attention and cooperation, psychomotor slowing, affect, hygiene, and speech pattern. A neurological examination should screen for focal deficits, increased muscle tone, cogwheeling, rigidity, or tremors. A detailed review of a comprehensive mental status and neurological examination in older adults is described in Chapter 12. Cardiac arrhythmias, carotid bruits, or abdominal or femoral bruits may suggest a predisposition to vascular dementia.

Cognitive testing can be readily performed in the primary care clinic setting using screening tests such as the Mini-Mental State Examination, the Clock Draw Test, and category fluency. In adults with high baseline cognitive functioning, however, these tests may be normal in the presence of obvious functional impairment necessitating referral to a neuropsychologist for more detailed testing. In those with lower educational levels, these cognitive screening tests may suggest impairment, but the history may not suggest any changes in functional status. Thus, it is critical to use age- and education-adjusted norms, and integrate historical information on baseline function to decide if further neuropsychological testing is warranted or if abnormal testing may actually represent the person's baseline status. In addition, screening for depression is a critical part of a memory assessment. Any suspicion of mood disturbances can be evaluated with a screening tool such as the Geriatric Depression Scale (GDS). These cognitive and affective screening tools can be easily administered by a variety of health care personnel, allowing for their use in a busy clinic setting.

Laboratory data can assist in identifying factors that may be contributing to cognitive decline. Rarely do these factors alone account for the overall cognitive changes that lead to the presentation of a patient with significant memory loss symptoms. Nevertheless, treating such factors may improve cognitive symptoms in patients with severe laboratory abnormalities, numerous comorbid illnesses, or in whom there is an underlying neurodegenerative process. Recommended laboratory tests include vitamin B-12, thyroid stimulating hormone (TSH), electrolytes, complete blood count, liver enzymes, homocysteine, red blood cell folate levels, and a cholesterol panel. If symptoms are atypical or if there are specific risk factors, then a serologic test for syphilis may be performed. In some European countries, routine assessment of cerebrospinal fluid (CSF) for β-amyloid and tau levels is done as part of the clinical evaluation. In the United States, CSF collection is usually reserved for ruling out Creutzfeldt–Jakob disease or other conditions such as normal pressure hydrocephalus (NPH). In most cases, it is recommended that some form of neuroimaging be obtained. Typical findings for AD on neuroimaging can range from a fairly normal scan to diffuse cerebral atrophy. A computed tomography (CT) of the head without contrast is usually sufficient to evaluate for significant cerebrovascular disease, brain tumors, subdural hematoma, or NPH. Magnetic resonance imaging (MRI) can provide more information if lacunar infarcts are suspected. In persons with suspected seizure disorder or Creutzfeldt–Jakob disease, an electroencephalogram (EEG) may be considered. Although positron emission tomography (PET) scans are used frequently in research settings, they are not yet advocated for regular use in clinical practice.

If a patient does not meet the criteria for AD yet clinical suspicion remains, either more detailed neuropsychological testing or repeat testing in 6 months may clarify the diagnosis as the symptoms progress. Persons with suspected MCI should be reassessed on an annual basis as 12% to 15% of individuals with this diagnosis progress to dementia each year. If the symptoms or course of the disease are atypical for AD, the level of functional decline is out of proportion to neuropsychological testing results, or if there are significant behavioral issues that need to be addressed, then referral to a geriatrician, neurologist, or psychiatrist with expertise in dementia is recommended.

Future Diagnostic Tools

Novel diagnostic tools are continually being investigated for use in the diagnosis of AD. Many of these tools are still mainly used in research settings, but are under continued study to evaluate their role in clinical practice. Current investigations are focusing on how to best identify biomarkers with strong relationships to clinically relevant outcomes in AD that could be used not only for diagnosis, but also for identifying asymptomatic persons at risk for AD. Neuroimaging modalities have shown great promise in documenting not only the late effects of neuronal damage in AD (regional and global cerebral atrophy), but also in identifying earlier in vivo pathology (such as in vivo amyloid imaging on PET) and the functional consequences of such pathology (activation patterns on functional MRI). CSF levels of Aβ and tau have been shown to predict risk for progression to AD in older adults and persons with MCI. With the recent advances in the safety and acceptability of lumbar punctures, CSF markers may eventually find their way into the clinical diagnostic workup of preclinical AD. Some blood and CSF inflammatory markers have also shown some value in predicting risk of cognitive decline. Future research is focusing how these biomarkers may be used in combination with cognitive tests to identify who is at greatest risk for AD, who would benefit most from preventive therapies, and how effective these therapies are in modifying the underlying disease process in asymptomatic individuals.

Managing patients with AD involves a comprehensive, multidisciplinary team approach including presentation of the diagnosis, initiation of medical therapy, assessment and treatment of concomitant depression and/or behavioral concerns, development of a social support network, education of patients and caregivers, provision of caregiver support, and initiation of appropriate safety measures. While not all medical centers have access to multidisciplinary team resources, effective care can still be given by focusing on providing established medical treatment, identifying a few strategies to maintain patient safety and providing basic education and caregiver support.

Presenting the Diagnosis

Presenting the diagnosis of AD to a patient is difficult, as it may generate significant emotional responses from the patient and their family and trigger fear of the future. Frequently, patients and family members suspect the diagnosis before it is presented, but how they respond to the news depends on personal coping mechanisms, cultural influences, family dynamics, and their preconceived understanding of AD. Clinicians may help patients and families adjust to this diagnosis by using an empathetic, yet honest approach and by providing them with educational and support resources, including those provided by agencies such as the Alzheimer's Association and the National Institute on Aging Alzheimer's Disease Education and Referral (ADEAR) Center. In addition, the clinician should emphasize the goals of diagnosing AD in order to take steps to protect the patient's memory, delay the progression of the disease, and to maintain the person's safety. In general, it is recommended to tell both the patient and family the diagnosis using the term “Alzheimer's disease”, thus, providing patients and families with a starting point for education. Encouraging both persons with the disorder and caregivers to utilize resources such as local support groups and the Alzheimer's Association is an important part of the patient management plan.

Treatment of Cognitive Symptoms

Acetylcholinesterase inhibitors (AChEIs) are the mainstay of therapy for AD, and until several years ago, were the only medications approved in the United States for the treatment of AD. AChEIs increase the levels of the neurotransmitter acetylcholine in neuronal synapses, thereby enhancing cholinergic activity in the affected brain regions. Although 18% to 48% of persons may experience improvements in cognition after taking these medications, the majority of patients do not have any noticeable improvement, but instead experience a plateau or slowing of their rate of cognitive decline. This lack of noticeable improvement has led to controversies regarding the benefit of using cholinesterase inhibitors. However, given the chronic nature of AD, delaying the progression of cognitive decline may lead to improvements in quality of life, reduced caregiver burden, and reduced economic cost associated with long-term care.

Four AChEIs have been approved for use in the United States by the Food and Drug Administration (FDA). These medications include tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®). Excessive gastrointestinal side effects have made use of tacrine less favorable given the improved safety and tolerability profiles noted with the newer agents. Dosing recommendations for the commonly used AChEIs are shown in Table 65-8. In general, the most common adverse effects associated with AChEI use are nausea, anorexia, and diarrhea. Gastrointestinal side effects may be alleviated by taking the medications with food. Sleep disturbances are also common, and may improve with altering the dosing schedule.

While used for many years in Europe, the United States' FDA-approved memantine (Namenda®) for use in moderate to severe AD in 2003. Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. At high concentrations, memantine can inhibit mechanisms related to learning and memory, but at lower concentrations, it can preserve or enhance memory in animal models of AD. Memantine can protect against the excitotoxic destruction of cholinergic neurons and may inhibit β-amyloid production. In persons with moderate to severe AD, memantine slows the progression of cognitive decline either alone or when used in conjunction with AChEIs. In addition, studies support that use of memantine showed better outcomes on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. While early trials show promising results, additional studies are needed before memantine can be recommended for early stages of AD. In most circumstances, it is appropriate to add this medication to cholinesterase inhibitor therapy in persons with moderate to severe AD. Current prescribing recommendations for memantine are shown in Table 65-8. In persons who do not tolerate cholinesterase inhibitors, memantine may be used as first-line therapy. With use of either AChEIs or memantine, clinicians should educate families on what to expect with use of the medications, namely that they work to delay the progression of the disease and not to significantly improve their cognition. Consideration should be given to the modest expected benefit and cost of both medications per month.

Disease-Modifying Therapies

Currently there are no FDA-approved disease-modifying therapies available, but research is making progress in identifying pathways that could serve as targets for such therapies. A variety of agents targeting β-amyloid metabolism are in various stages of development, including Aβ immunotherapy, agents inhibiting Aβ fibrillization and reducing soluble Aβ, selective amyloid lowering agents (SALAs), and β- and γ-secretase inhibitors. In addition, potential disease-modifying agents with known cardiovascular benefits, such as statins and omega-3 fatty acids, are currently being studied in large clinical trials.

While clinical trials have not conclusively shown that treating vascular risk factors delays the development or progression of AD, aggressive treatment of vascular risk factors in many patients with memory complaints, including those associated with AD, may be warranted. Vascular risk factor modification has known cardiovascular benefits that may lead to reduction of coronary artery bypass grafting, cerebrovascular disease, and stroke—factors strongly linked to cognitive decline. Trials are underway to clarify if vascular risk factor reduction and improved cerebral perfusion modify the course of AD. Until the completion of such trials, clinicians should follow established cardiovascular prevention guidelines for patients presenting with memory complaints, taking into account the patient's comorbid illnesses, quality of life, treatment costs, and life expectancy.

Preventive Strategies

Currently there are no established preventive therapies for AD. Evidence supports that future therapies that either delay or prevent the onset of AD may need to be started in midlife in high-risk populations in order to significantly influence the onset and course of the disease. As the underlying pathologic changes that eventually lead to clinical AD begin decades before the onset of symptoms, primary prevention trials with conversion to AD as their primary outcome may prove costly and time-consuming. Integrating biomarkers with strong relationships to clinically relevant outcomes into such primary prevention trials may allow for earlier identification of disease-modifying effects of potential preventive therapies. Given the multifactorial nature of AD, future preventive strategies will most likely target a variety of mechanisms related to disease progression, similar to that used in cardiovascular disease prevention. Some potential prevention therapies currently under investigation include vascular risk factor modification, anti-inflammatory medications, antioxidants, lifestyle interventions such as exercise, social engagement, and cognitive stimulation, and novel compounds targeting Aβ metabolism.

Behavioral Management

AD is frequently associated with behavioral disturbances that include agitation, emotional or physical outbursts, and sexual inappropriateness. Such behaviors may be more distressing to family and caregivers than the actual memory decline. Such behaviors may be managed by nonpharmacologic as well as pharmacologic interventions. Nonpharmacological therapies should be explored and exhausted before using pharmacologic therapy, unless the person's agitation threatens his or her safety or living situation. Addressing physical pain or other medical symptoms or distressing situations that could be contributing to agitation is key prior to any pharmacologic intervention. Identifying and correcting physical or emotional stressors may alleviate agitation. Potential medication side effects should be considered to see if they are contributing to agitation symptoms. After nonpharmacologic measures have been tried, consideration may be given to use of low-dose atypical antipsychotics taking into account potential risks associated with these medications. Selective serotonin reuptake inhibitors (SSRIs) may reduce symptoms of sexual inappropriateness. Wandering symptoms typically do not respond to pharmacologic therapy. Taking patients for a walk or giving them busy tasks to do may help reduce wandering. Frequently, it is the behavioral changes associated with AD and other dementias that are most distressing to family members and provide the greatest challenge for primary care physicians who are managing the care of persons with AD. Referral to a multidisciplinary memory disorders clinic is appropriate for patients with significant behavioral concerns. More information is dedicated to this topic in Chapter 73.

Safety Management

Reviewing common safety concerns in persons with dementia may help identify significant risks and provide an opportunity for educating family members and caregivers on what areas to monitor closely and what safeguards they can take to protect the person with AD. Some patients may require further evaluation to assess driving safety, which can be done through occupational or physical therapy departments or local driving schools. Pill boxes or other similar medication planners may facilitate correct administration of medications and allow family or caregivers to help in setting up the medications properly. Other safety concerns such as proper use of the stove, woodworking equipment, hunting rifles, etc. should be discussed and appropriate supervision arranged.

Caregiver Support

Evidence is accumulating that the effects of AD are felt not only by the patient but also by the caregivers. Caregivers have increased depression, missed work, and health problems compared to those not caring for a family member with dementia. Use of respite services from family, friends, neighbors, and local adult day centers may allow for caregivers to take the appropriate time needed to maintain their own health and social connections.

End‐of-Life Care

Upon diagnosis of AD, many patients and families have questions as to what to expect in the years ahead. As the rapidity of progression of AD may depend not only on genetic and environmental factors but also comorbid medical conditions, the course of decline can be difficult to predict in some persons. Once on medical treatment for AD and when all potentially reversible contributing factors have been addressed, obtaining repeat cognitive testing will give the clinician an idea of the trajectory of decline of the individual and help inform the family on what to expect in the years ahead. Providing information early in the disease course on end-of-life planning may help smooth this difficult transition later in the disease. Use of respite services and home health aides or family members may help the person with AD stay in the home longer. If the social network of the patient cannot support the patient as the care needs increase, then nursing home placement frequently is necessary. Involving hospice can help with symptom management late in the course of the illness. Involvement in Alzheimer support groups can provide support during the unique grieving process related to dementia, as family and caregivers watch the cognitive and personality transformations in their family member with AD.

Alzheimer's disease is the leading cause of dementia worldwide and, unless effective preventive strategies are identified, is expected to significantly increase in prevalence in the coming decades as the population ages. The diagnosis of AD remains a clinical diagnosis that requires careful history-taking, a physical examination, and cognitive testing to document a decline in cognitive and functional abilities. Ancillary laboratory and neuroimaging can help differentiate between various causes of memory loss and different types of dementia. Treatment for AD involves not only pharmacologic therapy with cholinesterase inhibitors and NMDA antagonists, but also careful assessment of safety, behavioral concerns, and education for the patient, family, and other caregivers. While preventive therapies have not yet been established, newly identified mechanisms of disease pathobiology are being targeted to develop effective novel therapies that could either delay or preferably arrest the progression of AD. Future research may help identify persons at highest risk for AD and develop treatment strategies targeting multiple mechanisms underlying the pathobiology of AD.