Alzheimer’s Disease Research Paper

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Alzheimer’s disease (AD) appears to be the most common cause of dementia, accounting for more than 50% of all dementia cases. AD is a progressive degenerative brain disorder that is characterized by neocortical atrophy, neuron and synapse loss, and the presence of senile plaques and neurofibrillary tangles. The plaques and tangles were first identified and reported in 1907 by the German physician and neuropathologist Alois Alzheimer. In his initial case he autopsied a 51-year-old patient who had recently died (from what we now term dementia) and discovered the presence of several histopathologic alterations, two of which were the neuritic plaques and the neurofibrillary tangles. Today they remain the two classic hallmarks of the disease and constitute the basis for the neuropathologic diagnosis of Alzheimer’s disease. The dementia of AD is characterized by severe amnesia with additional deficits in language, “executive” functions, attention, and visuospatial and constructional abilities. Patients may also experience changes in affect or personality and impairment of judgment. This research paper will provide an overview of the clinical, pathological, neuropsychological, and affective features associated with AD.

Alzheimer’s Disease Research Paper Outline

I. Clinical Features

A. Definition of Dementia

B. Diagnosis and Course of Alzheimer’s Disease

C. Epidemiology

1. Prevalence and Incidence of Alzheimer’s Disease

2. Risk Factors for Alzheimer’s Disease

D. Neuroimaging in Alzheimer’s Disease

II. Neuropathological Features

A. Neuritic Plaques

B. Neurofibrillary Tangles

C. Distribution of Neuropathological Changes

D. Major Neurochemical Alterations

E. Lewy Body Variant of Alzheimer’s Disease

III. Neuropsychological Deficits

A. Memory

1. Explicit Memory

2. Remote Memory

3. Episodic Memory

4. Semantic Memory

5. Implicit Memory

B. Attention/Concentration

C. Language

D. Spatial Cognition

E. Executive Function

IV. Affective and Personality Changes

V. Differentiation of Alzheimer’s Disease from Other Etiologies

A. Alzheimer’s Disease Versus Normal Aging

B. Alzheimer’s Disease versus Depression

C. Alzheimer’s Disease versus Subcortical Dementia

VI. Clinical Management of Alzheimer’s Disease

A. Management of Behavioral Disturbances

B. Pharmacologic Treatment

VII. Summary

I. CLINICAL FEATURES

A. Definition of Dementia

Dementia refers to a syndrome of acquired intellectual impairment of sufficient severity to interfere with social or occupational functioning, caused by brain dysfunction. According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, “Dementia of the Alzheimer’s Type” involves memory impairment and cognitive deficits in at least one other domain, demonstrated by aphasia, apraxia, agnosia, or impaired executive functioning. These symptoms must not be due to other neurological disorders, medical conditions resulting in dementia, or substance abuse. The cognitive impairments must have a gradual onset and a progressive decline and be severe enough to significantly interfere with social or occupational functioning. Furthermore, the cognitive impairment must represent a significant decline from a previously higher level of functioning, and it must not occur exclusively during the course of delirium (see Table I).

Prior to the DSM, however, in 1984, the Work Group on the Diagnosis of Alzheimer’s Disease, established by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), developed criteria for the clinical diagnosis of probable and possible AD (see Table II). Since then the NINCDS-ADRDA clinical criteria have been tested against autopsy verified diagnoses and found to be quite effective.ge length ranges between 7 and 10 years.

Table I DSM-IV Diagnostic Criteria for Dementia of the Alzheimer’s Type

1. The development of multiple cognitive deficits manifested by both
2. memory impairment (impaired ability to learn new information or to recall previously learned information);
3. one (or more) of the following cognitive disturbances:
4. aphasia (language disturbance);
5. apraxia (impaired ability to carry out motor activities despite intact motor function);
6. agnosia (failure to recognize or identify objects despite intact sensory function);
7. disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting).
8. The cognitive deficits in Criteria A 1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
9. The course is characterized by gradual onset and continuing cognitive decline.
10. The cognitive deficits in Criteria A1 and A2 are not due to any of the following:
11. other central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Parkinson’s disease, Huntington’s disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor);
12. systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B~2 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection);
13. substance-induced conditions.
14. The deficits do not occur exclusively during the course of a delirium.
15. The disturbance is not better accounted for by another Axis I disorder (e.g., Major Depressive Disorder, Schizophrenia)

Note. DSM-IV refers to the Diagnostic and Statistical Manual for Mental Disorders, 4th edition. From American Psychiatric Associaiton, 1994.

B. Diagnosis and Course of Alzheimer’s Disease

Because dementia is associated with more than 50 different causes of brain dysfunction (see Table IlI), and there are no known peripheral markets for Alzheimer’s disease, a definitive diagnosis continues to require histopathological verification of the presence of characteristic neurodegenerative abnormalities at autopsy (i.e., neuritic plaques and neurofibrillary tangles). However, documentation of the presence of dementia and the exclusion of all other known potential causes allows probable or possible Alzheimer’s disease to be clinically diagnosed during life with some certainty (i.e., current estimates are approximately 90% or better).

Patients with Alzheimer’s disease often live for many years following their diagnosis, dying eventually from conditions like pneumonia, sepsis, or other fatal conditions to which people of advanced age are prone. The duration of the disease from the time of diagnosis to death can be as little as 2 years or as long as 20 years or more, although the average length ranges between 7 and 10 years.

Table II NINCDS-ADRDA Criteria for Definite, Probable and Possible Alzheimer’s Disease

1. Definite Alzheimer’s disease:

Clinical criteria for Probable AD;

Histopathologic evidence of AD (autopsy or biopsy).

1. Probable Alzheimer’s disease:

Dementia established by clinical exam and documented by mental status testing;

Dementia confirmed by neuropsychological testing;

Deficits in two or more areas of cognition;

Progressive worsening of memory and other cognitive functions;

No disturbance of consciousness;

Absence of systemic or other brain diseases capable of producing a dementia.

III. Possible Alzheimer’s disease:

Atypical onset, presentation, or progression of a dementia syndrome with a known etiology;

A systemic or other brain disease capable of producing dementia is present but not thought to be the cause of the dementia;

A gradually progressive decline in a single intellectual function in the absence of any other identifiable cause.

1. Unlikely Alzheimer’s disease:

Sudden onset of symptoms;

Focal neurological signs and symptoms;

Seizures or gait disturbance early in the course of the illness.

From McKhann et al. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group, Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 34, 939-944.

Table III Causes of Dementia

1. Cerebral neuronaldegenerative disorders:

Alzheimer’s disease;

Pick’s disease;

Parkinson’s disease;

Huntington’s disease;

Progressive supranuclear palsy;

Dementia lacking distinctive histopathology.

1. Acquired cerebral disorders (some of which may be reversible):

Vascular dementia: Multi-infarct dementia; Binswanger’s disease;

Multiple sclerosis;

Intracranial neoplasms;

Trauma (e.g., subdural hematoma; dementia pugilistica; diffuse axonal injury);

Hydrocephalus;

Transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob disease).

III. Other potentially reversible dementias:

Metabolic disorders; Chronic drug intoxication; Alcoholism; Malnutrition (e.g., vitamin B12 deficiency);

Infections: HIV (AIDS); Neurosyphilis; Tuberculous or bacterial meningitis; Cryptococcosis; Acute viral encephalitis;

Dementia syndrome of depression.

Note: A complete listing would include many more disorders; those listed above serve to illustrate that dementia results from many different etiologies

Adapted from Berg & Morris, in Terry, Katzman, & Bick (1994).

C. Epidemiology

1. Prevalence and Incidence of Alzheimer’s Disease

Estimates of the prevalence of dementia vary widely due to differences in definitions, sampling techniques, and the sensitivity of instruments used to identify cases. However, Cummings and Benson calculated the average of prevalence estimates across studies and suggested that approximately 6% of persons over the age of 65 have severe dementia, and an additional 10% to 15% have mild to moderate dementia. Also, the prevalence of the syndrome of dementia doubles approximately every 5 years after age 65. Not surprisingly, the prevalence of dementia is higher among hospital and nursing home residents than among those living within the community.

2. Risk Factors for Alzheimer’s Disease

A number of reliable risk factors for Alzheimer’s disease have been identified. First, age is the single most important risk factor for dementia. Population-based studies in many different countries have confirmed that the prevalence of the most common causes of dementia (i.e., Alzheimer’s disease and vascular dementia) rises in an approximately exponential fashion between the ages of 65 and 85. Second, it has been suggested that women have a slightly greater risk for Alzheimer’s disease than men, due in part to its higher prevalence in women. The greater risk for women, however, may be a factor of their longer life expectancy, since incidence rates for Alzheimer’s disease have not shown differences between men and women.

Third, uneducated individuals over the age of 75 have about twice the risk for dementia as those who have completed at least a grade school education. Low lifetime occupational attainment, associated with little education, may also yield a greater risk for Alzheimer’s disease. Education and occupational achievement may act as a surrogate for brain or cognitive reserve that helps to delay the onset of the usual clinical manifestations of the disease.

Fourth, the risk of developing dementia is increased approximately fourfold by a family history of Alzheimer’s disease in a first-degree relative (i.e., mother, father, brother, or sister). Given some of the findings of specific point mutations on the amyloid precursor protein gene of chromosome 21 and linkage studies identifying gene loci on chromosomes 1, 14 and 19, there is now little question that this familial association is genetically based. Furthermore, the epsilon-4 allele of the apolipoprotein E gene (ApoE-e4) located on chromosome 19 has recently been identified as another risk factor for dementia because of its over-representation in patients with Alzheimer’s disease.

Finally, the risk of developing Alzheimer’s disease is doubled for individuals with a history of a single head injury that led to a loss of consciousness or hospitalization. This finding, however, may be confined to those Alzheimer’s patients with previous head injuries who also carry at least one ApoE-e4 allele. Recent research has demonstrated that individuals with a history of head injury who lack the presence of the ApoE-e4 allele are not at increased risk for Alzheimer’s disease.

If one assumes that these aforementioned risk factors are simply additive at the population level, then the attributable risk of developing Alzheimer’s disease from these known factors appears to be between 40% and 50% (and probably more given the recent addition of ApoE-associated risk).

Thus, current views suggest that Alzheimer’s disease is a chronic disease, much like cancer or heart disease, in which an individual is predisposed by genetic factors, traumatic events, or other unknown factors toward entering a malignant phase. Intracellular events will eventually lead to neuritic degeneration, the formation of neurofibrillary tangles, and neuron and synapse loss. Over a period of time, the neural degeneration gradually reaches a level that initiates the clinical symptoms of the dementia syndrome. This framework for understanding the development of AD suggests that cognitive deficits associated with the disease also appear gradually.

D. Neuroimaging in Alzheimer’s Disease

A variety of neuroimaging techniques have been used to study and characterize Alzheimer’s disease. Some of the most recent techniques include structural and volumetric analysis of the brain with magnetic resonance imaging (MRI), computation of regional cerebral metabolism with positron emission tomography (PET), regional cerebral blood flow with single photon emission computed tomography (SPECT), and determination of regional biochemical concentrations with magnetic resonance spectroscopy (MRS).

MRI studies of Alzheimer’s disease patients reveal a decrease in brain volume, apparently due to gyral atrophy and ventricular dilatation. However, gyral atrophy and enlarged ventricles are also found in normally aging brains, lending minimal diagnostic value to structural images early in the course of the disease. Future research targeting hippocampal or entorhinal cortex, however, may yield more sensitivity to early stage Alzheimer’s disease.

Functional imaging studies with PET and SPECT have found significant differences between Alzheimer’s disease patients and healthy older adult control subjects. Temporoparietal and frontal cortical regions have shown significant glucose metabolic reductions, with relative sparing of visual and sensorimotor cortex. Furthermore, significant relationships have been found between neuropsychological impairment in AD and the degree of hypometabolism found by PET. In addition, Haxby (in Rapoport, Petit, Lays, and Christen) measured cerebral metabolism with PET in Alzheimer’s patients and found differing patterns of decreased metabolism in the association cortex. The individual patterns of decreased metabolism correlated with neuropsychological test scores purported to reflect processing in particular brain regions. The decreased neocortical metabolism was found even in patients in the earliest stages of dementia of the Alzheimer type, in whom neuropsychological testing revealed no deficits other than amnesia. This finding suggests that PET imaging can be useful in the early detection of AD.

As a marker of cerebral blood flow in Alzheimer’s disease, SPECT also demonstrates similar regional reductions to that of PET, although its spatial resolution is not as high. However, its significantly lower cost allows for its more widespread use. In addition, SPECT studies have attempted to trace neurotransmitter receptor changes in Alzheimer’s disease patients (e.g., muscarinic receptors; dopaminergic D2 receptors), although results have been mixed to date.

Findings in MRS studies suggest that this technique may also be sensitive to the early detection of Alzheimer’s disease. For example, an increase in the biochemical concentration of myo-inositol has been found in patients with mild to moderate Alzheimer’s disease. Myo-inositol serves several functions in the brain, one of which may involve the deposition of neuritic plaques characteristic of Alzheimer’s disease. Increases in myo-inositol concentration have not been found in patients with other dementing illnesses or in normally aging individuals.

Thus, preliminary findings from a number of recent studies suggest that MRI, PET, SPECT, and perhaps MRS can provide complementary information to the usual diagnostic procedures and may contribute to the early and more specific detection of the disease. It should be emphasized, however, that although the usefulness of structural or functioning neuroimaging procedures appear promising, each of these costly techniques remains experimental and has not been shown to be as accurate as the clinician’s judgment in the differential diagnosis of Alzheimer’s disease. Future longitudinal studies are needed to determine the prospective accuracy of early diagnosis through structural and functional neuroimaging techniques, particularly studies that will be able to provide neuropathologic confirmation.

II. Neuropathological Features

Alzheimer’s disease is primarily characterized by two particular histological findings in the brain: neuritic plaques and neurofibrillary tangles. Other associated features include neurotransmitter reductions, particularly acetylcholine and norepinephrine, as well as neuron and synapse loss.

A. Neuritic Plaques

Neuritic plaques are complex deposits of amyloid protein and glial cells. These extracellular deposits collect most heavily in portions of the entorhinal cortex and hippocampal formation, two brain areas critical for memory and learning of new information. Neuritic plaques are also found throughout the cortical mantle of the neocortex, with a predilection for association regions.

B. Neurofibrillary Tangles

Neurofibrillary tangles are networks of insoluble proteins which collect inside neurons and result in a breakdown in the structure of the neuron’s cytoskeleton. The protein networks become so complex over time that normal cell metabolism and nutrient flow become impossible and the cell eventually dies. As with plaques, tangles accumulate most densely in the entorhinal and limbic regions of the brain, although tangles are also found in many structures that project to the cerebral cortex such as the nucleus basalis of Meynert, locus ceruleus, midline thalamic nuclei, as well as in some hypothalamic nuclei and the ventral tegmental area, and dorsal raphe nucleus.

C. Distribution of Neuropathological Changes

In addition to plaques and tangles, pathological changes in Alzheimer’s disease include neocortical atrophy, neuron loss, and synapse loss. These changes occur primarily in the hippocampus, entorhinal cortex, and in the association cortices of the frontal, temporal, and parietal lobes. Although the temporal progression of the neuropathological changes of Alzheimer’s disease are not fully known, recent studies suggest that the hippocampus and entorhinal cortex are involved in the earliest stage of the disease, and that frontal, temporal, and parietal association cortices become increasingly involved as the disease progresses.

D. Major Neurochemical Alterations

In addition to these cortical changes, subcortical neuron losses occur in the nucleus basalis of Meynert and in the locus ceruleus, resulting in a decrement in neocortical levels of cholinergic and noradrenergic markers, respectively.

E. Lewy Body Variant of Alzheimer’s Disease

Another neuropathologic condition in demented patients is characterized by the typical cortical distribution of senile plaques and neurofibrillary tangles of Alzheimer’s disease, the typical subcortical changes in the substantia nigra, locus ceruleus, and dorsal vagal nucleus of Parkinson’s disease, and, in addition, Lewy bodies that are diffusely distributed throughout the neocortex. Although only recently identified, this neuropathologic condition is not rare and may occur in approximately 25 % of all demented patients.

The clinical manifestation of this disorder, which is sometimes known as the Lewy body variant of Alzheimer’s disease, is similar to that of Alzheimer’s disease in many respects, and these patients are often diagnosed with probable or possible Alzheimer’s disease during life. However, retrospective studies indicate that Lewy body variant of Alzheimer’s disease may be clinically distinguishable from “pure” Alzheimer’s disease. While both disorders are associated with a severe and progressive dementia, there may be an increased prevalence of mild extrapyramidal motor findings (e.g., bradykinesia, rigidity, masked facies) and hallucinations in patients with Lewy body variant of Alzheimer’s disease, as well as a more rapid course.

III. Neuropsychological Deficits

A. Memory

Failure of recent memory is usually the most prominent feature during the early stages of Alzheimer’s disease. Accordingly, much of the neuropsychological research concerning the early detection of Alzheimer’s disease has focused on memory. Numerous studies have shown that measures of the ability to learn new information and retain it over time are quite sensitive in differentiating between mildly demented patients with clinically diagnosed AD and normal older adults.

1. Explicit Memory

Explicit, or declarative, memory, which refers to the conscious recollection of previously acquired information, is the type of memory assessed by classic, clinical tests of recall and recognition. One common dichotomous classification of explicit memory, the distinction between episodic and semantic memory, is based on the type of information stored in memory. Episodic memory contains context-linked information in which retrieval depends upon spatial and temporal cues. For example, remembering whether one took one’s last dose of a medication requires retrieval of an episodic memory (i.e., where and when one took the medicine). Semantic memory, in contrast, refers to information that is context-free and usually overlearned. Thus, recollection that 3 x 2 = 6, that Hawaii is in the Pacific, and that the colors of the American flag are red, white, and blue, can be achieved without recalling the episode (or spatiotemporal context) in which that information was acquired.

Although of general heuristic value in understanding anterograde amnesia (i.e., impaired learning and retention of new information after occurrence of cerebral insult), the episodic-semantic distinction’s application to retrograde amnesia (i.e., impaired recollections of information acquired before cerebral insult) is more problematic. For this reason, loss of remote memory (or retrograde amnesia) in Alzheimer’s disease is discussed briefly before episodic and semantic memory are discussed.

2. Remote Memory

Retrograde amnesia is temporally graded in early Alzheimer’s disease. In other words, events from the distant past, such as the patient’s childhood, are remembered more easily than events from more recent past, such as middle adulthood. As the disease progresses into later stages, the patients’ retrograde amnesia loses its temporal gradient, and a deficit is seen in retrieval of all explicit memory, regardless of when the information was encoded.

3. Episodic Memory

Episodic memory involves the storage and recollection of temporally dated autobiographical events that depend upon temporal and/or spatial contextual cues for their retrieval. Memory difficulties in the earliest stages of Alzheimer’s disease become apparent when patients are confronted with everyday tasks requiring the use of episodic memory, such as tracking medication regimens, paying bills on schedule, and keeping abreast of recent events in the news. Because of its prevalence in the early stages of AD, episodic memory disturbance is considered to be a necessary (but not sufficient) feature for the clinical diagnosis (see Table I).

Memory impairments, even in patients in the early stages of the disease, are apparent on clinical and experimental memory tasks that require the learning and retention of either verbal or nonverbal information over a series of trials. This severe anterograde amnesia appears to primarily result from a failure in consolidation that is mediated by damage to the hippocampus and entorhinal cortex, and neurotransmitter changes in the cholinergic system. This inability of Alzheimer’s patients to transform to-be-remembered information into a form suitable for long-term retention cannot be circumvented by effortful or elaborative processing at the time of acquisition. This contrasts with normal elderly, who have been shown to benefit from engaging in elaborative or semantic processing of information during the study phase of free recall tasks.

Further evidence of patients’ deficiencies in storage (i.e., consolidation) is provided by their severe impairments on recognition as well as on recall tasks and by their very limited improvement in acquisition over repeated learning trials. The numerous observations that Alzheimer’s patients tend to recall only the most recently presented stimuli (i.e., heightened recency effects) support the notion that these patients have great difficulty in transferring information from short- to long-term storage.

In addition to their difficulties in storing new information, patients also tend to evidence rapid forgetting of what little they do initially learn. The rapid forgetting is apparent for both verbal and nonverbal information and has been shown to be even more rapid in Alzheimer’s disease than in amnesia. Recent findings suggest that this feature of memory loss is most important for the early and differential diagnosis of Alzheimer’s disease and can be obtained through measures of delayed recall (e.g., number of words recalled after a few minutes delay) and savings scores (e.g., percent retained over a period of time).

Intrusion errors, or errors representing the intrusion of previously learned information into the attempted recall of new material, represent a consistent behavioral marker of dementia in Alzheimer’s disease and are evident on tests of memory for verbal and figural information. However, some caution should be exercised when using such errors in a clinical setting. Intrusion errors in isolation do not represent an exclusive finding in AD since they also occur in patients with other forms of dementia (e.g., Huntington’s disease) and in some patients with circumscribed amnesia (e.g., Korsakoff’s syndrome). Furthermore, measures of error types have not proven to be the most sensitive cognitive indices for the detection of dementia. Thus, the occurrence of intrusion errors on episodic memory tests should be considered one indicator of a significant memory disturbance and should serve to initiate a thorough search for the processes underlying the patient’s impairments.

4. Semantic Memory

While the episodic memory impairment in Alzheimer’s disease has been studied in great detail, the semantic memory deficits associated with the disorder have only recently been extensively investigated. It has been known for some time through clinical characterizations of Alzheimer’s disease that language deficits, such as word-finding difficulties in spontaneous speech and mild anomia, often occur during the course of the disease. Similarly, decrements in patients’ general fund of knowledge concerning common facts of history, geography, arithmetic, and science have been observed and reported. Despite these observations, systematic study of patients’ semantic knowledge was lacking. Fortunately, investigators have now begun to examine the language and knowledge deficits in Alzheimer’s disease within the framework of current models of the representation of semantic knowledge that were developed in the field of experimental cognitive psychology.

It is often assumed that semantic knowledge is organized as a complex network of associated concepts, and that within the network, concepts that have many attributes in common are more strongly associated than those that share fewer attributes. These strongly related concepts are thought to form conceptual categories made up of exemplars that share many attributes. The attributes not only provide a means of grouping concepts into categories, but also provide a means of distinguishing among the various exemplars that constitute a given category. Thus, dog and lion are both categorized as animals because they share attributes such as being alive, being mobile, and being able to reproduce, but they can be distinguished from each other by such attributes as domesticity, size, and shape. A number of recent investigations suggest that this organization of semantic memory is disrupted in patients with AD, possibly due to damage to the association cortices that are thought to store the concepts and associations that constitute semantic knowledge.

There are a number of characteristics of the semantic memory impairment in Alzheimer’s patients. First, patients exhibit a disproportionately severe fluency deficit when generating exemplars from a semantic category (e.g., animals) as compared to generating words from a phonemic category (e.g., words beginning with “F”). Their category fluency performance is characterized by an increased propensity to produce category labels relative to specific exemplars. Second, AD patients are impaired on object-naming tasks and produce a significantly greater proportion of semantically based errors than normal older adults and patients with Huntington’s disease. In particular, Alzheimer’s patients tend to refer to specific objects by their superordinate category names (e.g., “bird” for pelican). Third, patients with Alzheimer’s disease demonstrate a deficit in sorting items on the basis of subordinate, but not superordinate, attributes. Fourth, there is a correspondence in items missed by AD patients across tasks designed to access semantic knowledge through different modes of input and output. Lastly, there is a deterioration in the organization of semantic knowledge in patients that can be consistently demonstrated by alterations in cognitive maps that reflect the semantic relationships used in categorizing concepts.

Taken together, these findings suggest that there is a true loss of semantic knowledge in Alzheimer’s disease, and that the nature of semantic memory deterioration in AD is consistent with a bottom-up breakdown in which specific attributes of a semantic category are lost before more general superordinate knowledge. This loss of semantic knowledge disrupts the normal organization of semantic memory in AD patients and results in aberrations in their network of semantic representations.

5. Implicit Memory

Tests of episodic and semantic memory generally require that prior episodes or events, or previously acquired knowledge, be explicitly and consciously recollected. However, recent research indicates that some forms of learning and memory occur implicitly, without conscious recollection. This implicit knowledge is expressed indirectly throughout the performance of the specific operations comprising a task. Classical conditioning, lexical and semantic priming, motor skill learning, and perceptual learning have all been considered forms of implicit memory. In all of these instances, individual’s performances are facilitated “unconsciously” by the prior exposure of stimulus material.

As is the case for episodic and semantic memory, the distinction between explicit and implicit memory receives neurobiological and neuropsychological support from studies of patients with amnesia. Severely amnesic patients are impaired on tests of explicit memory, but perform normally on implicit memory tests. For example, amnesic patients can acquire and retain motor skills (e.g., playing a series of notes or tune on a piano) without any memory for the training experiences. Similarly, amnesic patients will often evidence decreased visual identification thresholds for previously presented words they cannot recall or recognize on explicit memory tests. It is presumed that the initial visual presentation of the words activated some unconscious trace that later facilitated the visual identification of the stimuli without affecting conscious attempts to recollect the materials.

Although the specific neurological substrates of explicit memory have been extensively described, little attention has been given to the brain structures responsible for various forms of implicit memory. While damage to the mesial region of the temporal lobes, the medial diencephalon, and the basal forebrain all result in severe impairments in explicit memory, little is known about the brain structures that mediate various forms of verbal and pictorial priming and skill learning. However, recent studies of the performances of Alzheimer’s and Huntington’s patients on lexical and pictorial priming as well as on skill-learning tasks have resulted in some new insights into this neuropsychological issue. The findings emanating from these studies have indicated that Alzheimer’s and Huntington’s patients matched for overall level of cognitive decline can be dissociated with implicit memory tasks that involve the priming of semantic knowledge and the initiation of central motor programs. This double dissociation suggests that portions of the association cortex and the basal ganglia mediate quite different forms of implicit memory. More specifically, the association cortices, which are damaged in Alzheimer’s disease, appear to be vital for implicit tasks that seem to rely upon the integrity of semantic knowledge, whereas the basal ganglia, which are damaged in Huntington’s disease, are most important for implicit tasks that involve the generation and modification of central motor programs to guide behavior.

B. Attention/Concentration

In addition to memory deficits, patients with Alzheimer’s disease also experience deficits in attentional and concentration abilities. It has been hypothesized that impairment in working memory results in difficulty maintaining attention to complex or shifting sets. In fact, subtle impairments in the earliest stages of AD may be seen on complex attentional tasks depending upon divided and shifting attention. Some patients in the early disease stages do not have attentional problems, but such deficits typically emerge and increase in severity as the disease progresses.

C. Language

Deficits in some aspects of language increase in severity throughout the course of Alzheimer’s disease. Certain language abilities tend to remain intact, however. Patients exhibit little impairment in articulation abilities, and they also have little of the severe grammatical deficits seen in other neurological disorders, such as Broca’s aphasia. With relatively few phonetic and syntactic deficits, the fluency of patients’ spontaneous speech and oral reading typically remain intact. In the later stages of the disease, some patients have difficulty producing complex syntax in spontaneous speech. Similarly, patients’ auditory comprehension of complex sentences with abstract components may become impaired as dementia increases in severity.

Difficulty with word finding is seen early in Alzheimer’s patients, although usually not as early as memory deficits. Patients experience a progressive anomia directly evident on tests of confrontation naming, such as the Boston Naming Test. Patients often circumlocute as they search for particular targets. They also make semantic errors, as described earlier, such as providing picture names that are actually the categories to which pictures belong (e.g., saying “bird” for the target “pelican”) and providing names for pictures that are meaningfully associated to the target (e.g., saying “sweeping” for the target “broom”).

Alzheimer’s patients also exhibit semantic deficits on tests of category fluency. This is a disproportionately severe fluency impairment exhibited by patients when generating exemplars from a specific category compared to generating words that begin with a particular letter.

D. Spatial Cognition

Impairments in spatial cognition are evident in some patients with mild Alzheimer’s disease, and in nearly all patients in the later stages of the disease. Degeneration of the parietal lobe is the likely cause of these deficits. Early in the disease, patients experience a more severe and progressive disorientation in space relative to time. This results in the wandering behavior and confusion about location seen frequently in patients. Spatial disorientation appears to be a result of combined impairment in both memory and visuospatial skills.

A progressive decline in drawing ability is also characteristic of patients with Alzheimer’s disease. An early onset of impairment is often seen on complex tasks. For example, patients are significantly impaired compared to healthy older adults when asked to draw a clock or when copying complex geometric designs such as the Rey-Osterrieth Complex Figure. In their drawings, patients tend to make more omission, confabulatory, and perseverative errors, and when drawing a clock AD patients often make conceptual errors. Finally, qualitative differences in the types of errors made on tests of visuoperceptive ability may help differentiate normal aging from patients in the early stages of Alzheimer’s disease.

E. Executive Function

Although patients are typically aware of their earliest symptoms, such as memory problems, there is an increasing loss of insight as Alzheimer’s disease progresses. Gradually patients are unable to recognize their cognitive impairments and to judge the quality of their own behavior. In addition, preservations and intrusions are evident in patients’ daily behavior early in the disease. Progressive decline in patients’ executive function is also seen in their ability to think abstractly and to solve problems, with deficits occurring early in the course of the disease.

IV. Affective and Personality Changes

Personality changes represent one of the most common alterations in Alzheimer’s disease, affecting upward of 75% of patients at some time during the course of the disease. Changes can vary widely in a number of ways such as disengagement or disinterest in one’s surroundings, disinhibition or inappropriate social behavior, psychosis, delusions, or other disruptive behaviors. Affective changes can occur as well. Although major depression is uncommon, dysphoric affect can occur with some regularity in Alzheimer’s disease (e.g., 50% report symptoms of sadness or demoralization), and anxiety is reported in approximately 50% of patients as well. Hallucinations, which occur in approximately 25 % of Alzheimer’s cases, are typically visual or auditory in nature, although gustatory, olfactory and haptic hallucinations have also been reported. Delusional preoccupation is not uncommon either. For example, “capgras syndrome,” in which the individual believes that his or her family member has been replaced by an imposter, represents one of the most common types of delusional disturbances. Finally, agitation is also one of the most frequently cited symptoms in patients (up to 75 %), which creates tremendous burden for caregivers. In sum, abnormal behaviors as a consequence of affective or personality changes in Alzheimer’s patients are quite common and typically give rise to more caregiver-related burden than do the cognitive sequelae.

V. Differentiation of Alzheimer’s Disease from Other Etiologies

A. Alzheimer’s Disease versus Normal Aging

Individuals in the early stages of Alzheimer’s disease are by definition impaired in two or more cognitive functions, although the most effective neuropsychological measures for distinguishing between these subjects and healthy older individuals are those that assess the ability to learn new information and retain it over time. For example, in direct comparisons of the effectiveness of measures of learning, retention, confrontation naming, verbal fluency, and constructional ability for differentiating between very mildly demented patients with probable AD and normal elderly individuals, a number of studies have demonstrated the highest diagnostic accuracy (approximately 90%) with delayed free recall measures. Similar results have also been obtained with confirmation by subsequent postmortem histopathologic evidence of Alzheimer’s disease in patients who were psychometrically classified as mildly impaired and in none of those classified as normal elderly.

Although measures of learning and retention are the most effective neuropsychological indices for differentiating between mildly demented and normal elderly individuals, measures of language, “executive” functions, and constructional abilities also have some diagnostic value. For example, performances of mildly demented patients with probable Alzheimer’s disease and normal elderly control subjects on several types of verbal fluency tasks demonstrate that the semantic category fluency task has greater than 90% sensitivity and specificity for the diagnosis of dementia. Similarly high sensitivity and specificity rates for the differentiation of normal older adults from those patients with Ad has been shown on tests of executive function such as the Stroop Color-Word test, Trailmaking, and on a modified version of the Wisconsin Card Sorting Task.

In addition to detecting subtle cognitive impairment in the early stages of a dementing illness, neuropsychological testing is important for tracking the progression of cognitive decline throughout the course of the disease. Several studies have shown that brief, standardized mental status examinations can effectively document general cognitive decline. Nevertheless, despite the effectiveness of mental status examinations for assessing general cognitive decline, comprehensive neuropsychological testing is often required to track the progression of dementia, particularly when it is necessary to detect changes in specific cognitive domains, or to evaluate the efficacy of a potential treatment. A number of studies have shown that tests of memory and other neuropsychological functions are sensitive to the cognitive decline that occurs between the mild and moderate stages of dementia severity. However, these studies have also shown that neuropsychological measures other than memory are most effective in this regard. Because even mildly demented patients often have severe memory deficits that result in near floor performance on tests of free recall, measures of recognition memory, verbal fluency, confrontation naming, and praxis may be better studied for staging dementia severity or tracking its progression.

B. Alzheimer’s Disease versus Depression

A continuing problem for health care professionals involves the diagnosis of older adults who present with signs of both cognitive impairment and depression. In these individuals, a determination must be made whether the patient is experiencing cognitive difficulty secondary to a mood disorder or whether the patient has developed a depressive syndrome secondary to a dementing illness such as Alzheimer’s disease.

Kaszniak and Christenson (in Storandt and VandenBos) highlight that research findings concerning neuropsychological test performance of patients with depression and cognitive impairment remains small and difficult to interpret. The “dementia syndrome of depression” likely represents a heterogeneous mixture of different patient groups. Some of these patients may have a combination of a primary dementing illness and depression, and they will remain cognitively impaired following effective treatment of their depression. Others may have cognitive impairment secondary to their depression and will demonstrate improvement of both cognition and mood following effective treatment. However, even among this second group, some patients may manifest a clear progressive dementia over time despite initial improvements in mood. Thus, it is not surprising to find that depressed patients form clusters of different patterns of performance on various neuropsychological tests, such as the California Verbal Learning Test. In reviews of the research literature relevant to differentiation of dementia from depression (see Kaszniak and Christenson), attempts have been made to determine those quantitative and qualitative aspects of neuropsychological test performance that may be helpful in this diagnostic task.

Kaszniak and Christenson caution that these neuropsychological test features should be viewed as guidelines for increasing or decreasing suspicion of a patient having Alzheimer’s disease versus the dementia syndrome of depression, rather than as providing definitive diagnoses. Recent research suggests that differentiating patients with dementia syndrome of depression from those with vascular dementia due to subcortical infarctions, or other subcortical dementias, may be particularly difficult. Investigators have found that, among a group of depressed patients, the California Verbal Learning Test revealed a subgroup demonstrating the same pattern of deficits as those seen in patients with Huntington’s disease, which is typically regarded as a prototypical subcortical dementing illness.

C. Alzheimer’s Disease versus Subcortical Dementia

A considerable amount of recent research has been directed toward identifying the pattern of cognitive changes that might distinguish between Alzheimer’s disease and dementia associated with other neurodegenerative diseases. Much of this research has been carried out within the framework of a “corticalsubcortical” distinction, which holds that different patterns of primary neuropsychological deficits are associated with neurodegenerative diseases that predominately involve regions of the cerebral cortex (e.g., Alzheimer’s disease, Pick’s disease) or that have their primary locus in subcortical brain structures (e.g., Huntington’s disease, Parkinson’s disease, progressive supranuclear palsy). Studies that address this distinction usually compare and contrast neuropsychological test performance of patients with AD (a prototypical cortical dementia) and that of patients with Huntington’s disease (a prototypical subcortical dementia).

In addition to these differences in the general neuropsychological features of Alzheimer’s disease and dementia associated with Huntington’s disease, numerous studies utilizing concepts and experimental procedures of cognitive psychology suggest that there is a fundamental difference in the nature of the memory impairment that occurs in each disorder. Alzheimer’s patients exhibit a severe deficit in episodic memory (i.e., temporally dated autobiographical episodes that depend upon contextual cues for their retrieval) that appears to result from ineffective consolidation (i.e., storage) of new information, whereas the memory disorder of Huntington’s patients is thought to result from a general difficulty in initiating a systematic retrieval strategy when recalling information from either episodic or semantic memory (i.e., overlearned facts and concepts that are not dependent on contextual cues for retrieval).

Although Huntington’s patients also exhibit difficulty in learning and recalling information on free recall tasks, evidence of a general retrieval deficit is provided by a marked improvement in their performance when memory is tested with a recognition format, and by their ability to retain information over a delay in near normal fashion, quite unlike that of AD patients.

Patients with cortical and subcortical dementia syndromes can also be differentiated by their performances on tests of remote memory. Several studies indicate that in early stages of DAT, remote memory loss is temporally graded with memories from the distant past (i.e., childhood and early adulthood) better remembered than memories from the more remote past (i.e., mid and late adulthood). In contrast, patients with Huntington’s disease or Parkinson’s disease suffer only a mild degree of retrograde amnesia that is equally severe across all decades of their lives. These results suggest that the remote memory deficit of patients with subcortical dementia is another reflection of a general retrieval deficit that equally affects recollection of information from any decade of their lives, whereas the temporally graded remote memory loss of Alzheimer’s patients is indicative of a failure to adequately consolidate information through repeated processing, rehearsal, or re-exposure.

In addition to their distinct patterns of performance on tests of episodic and remote memory, patients with cortical and subcortical dementia syndromes differ markedly with regard to presence and severity of language deficits. AD patients, for example, are noted for mild anomia and word-finding difficulties in spontaneous speech, and evidence suggests that this deficit is indicative of a loss of semantic knowledge and a breakdown in the organization of semantic memory. In contrast, patients with Huntington’s disease generally retain their language abilities. For example, these patients perform at near normal levels on tests of confrontation naming, and the errors they produce are often visuoperceptually based rather than semantically based. Although Huntington’s patients perform poorly on tests of verbal fluency, they are equally impaired regardless of the semantic demands of the task, suggesting that their poor fluency performance is more likely to be related to their general deficiency in initiating an effective retrieval strategy than to a true language deficit.

Another major distinction that can be drawn between patients with cortical and subcortical dementia syndromes is the different patterns of spared and impaired abilities they exhibit on various implicit memory tasks. Implicit memory has been described as being mediated by a distinct memory “system” independent from the conscious, episodic memory system. Neuropsychological and neurobiological evidence for this distinction is provided by numerous studies that have demonstrated preserved implicit memory in patients with severe amnesia arising from damage to hippocampal formation or to diencephalic brain regions.

Studies comparing patients with cortical and subcortical dementia on various priming tasks have shown that Alzheimer’s patients, but not Huntington’s patients, are significantly impaired on lexical, semantic, and pictorial priming tests. In contrast to the priming results, Huntington’s patients, but not Alzheimer’s patients, are impaired on motor skill learning, prism adaptation, and weight biasing tasks that involve generation and refinement (i.e., learning) of motor programs to guide behavior.

VI. Clinical Management of Alzheimer’s Disease

A. Management of Behavioral Disturbances

Alzheimer’s patients experience a variety of behavioral disturbances, which place great demands on caregivers in finding ways to effectively manage them. Psychiatric symptoms, wandering, and aggressive behaviors, ranging in severity, are common in patients. Patients may also become frustrated with their own impairments, for example, when trying to communicate or remember things. More severe changes in behavior are evident in the later stages of the disease, when patients are no longer able to handle their daily functioning needs, like eating, bathing, and toileting.

Management of these behavioral symptoms is often attempted by teaching caregivers behavioral modification techniques. Simplifying the stimulation available in patients’ environments, offering frequent reminders and reassurances, abiding by a consistent routine, and providing patients with enjoyable activities also help to keep the patient comfortable and content. To aid in coping with the stress of managing these symptoms, support groups for caregivers of Alzheimer’s patients are available nationwide. Because the responsibilities of caregiving for patients with AD are so great, however, the services offered by nursing homes often provide care for patients whose families are unable to handle the tasks on their own.

B. Pharmacologic Treatment

Psychotropic medications may be used to manage behavioral disturbances in Alzheimer’s patients. Antipsychotic drugs, such as Haldol, can minimize delusions, hallucinations, and agitation experienced by patients. Antidepressants, like Prozac, are used to improve patients’ moods and energy level. Valium and other anti-anxiety medications are prescribed to manage agitation and anxiety. Unfortunately, many psychiatric medications can also further compromise cognitive functioning, especially those with strong anticholinergic properties.

Recent research has focused on testing medications that may slow the progression of Alzheimer’s disease. Tetrahydroaminoacridine (THA), or Cognex, is a drug that purportedly suppresses the breakdown of acetylcholine in the hopes of slowing patients’ cognitive decline. Unfortunately, Cognex, the first drug approved for the treatment of Alzheimer’s disease, has not appeared to be clinically effective in the majority of patients for whom it is prescribed. Other current research is focusing on the role of neurotrophic factors, estrogen, calcium, and antioxidants in the progression of Alzheimer’s disease.

VII. Summary

Alzheimer’s disease is the most common cause of dementia, currently affecting nearly 4 million people in the United States. Estimates project that its prevalence will rise to approximately 14 million by the year 2050. Whether one views AD from an individual, family, or public health perspective, its devastating consequences will continue to escalate and affect us either directly or indirectly in many ways. In short, Alzheimer’s disease will increasingly become the dominant disorder in late life.

Cognitive changes associated with this dementia include progressive impairments in memory, attention, language, spatial cognition, and executive function, some of which occur in the earliest stages of the disease. Patients also experience changes in behavior, affect, and personality. The cognitive, behavioral, and affective changes result in an increasing dependency of Alzheimer’s patients on others in their day-to-day functioning.

The disease is characterized by a number of neuropathological changes, including the presence of neurofibrillary tangles and neuritic plaques, loss of neurons and synapes, neocortical atrophy, and alterations in neurotransmitter levels. A definitive diagnosis can be made only at autopsy or with a brain biopsy, upon detection of sufficient numbers of neurofibrillary tangles and neuritic plaques. As no effective treatment or cure for Alzheimer’s disease is currently available, strategies for the management of disease symptoms focus on behavioral modification and the use of psychiatric medications where appropriate.

Fortunately, sustained efforts on a number of research fronts (i.e., molecular biological, genetic, cognitive, and behavioral) have helped to improve our understanding of Alzheimer’s disease and ultimately may lead to effective treatments for the prevention and cure of this complex and devastating disease.

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