Objectives: Upon Completion of this activity, the participant will be able to:

1. Understand the genetic factors associated with Alzheimer's Disease, supported by statistical data.
2. Know the symptoms of Alzheimer's Disease and how to diagnose the disease.
3. Speak knowledgeably about methods of treatment for Alzheimer's Disease

Background: Alzheimer disease (AD) is the most common cause of dementia, which is an acquired cognitive and behavioral impairment of sufficient severity to markedly interfere with social and occupational functioning.

AD affects approximately 5 million people in the United States and more than 30 million people worldwide. A larger number of individuals have decreased levels of cognitive impairment (eg, minimal cognitive impairment), which frequently evolves into a full-blown dementia, thereby increasing the number of affected persons. The prevalence of AD is expected to substantially increase in this century because it preferentially affects the elderly, who constitute the fastest growing age group in many, especially industrialized, countries. Statistical projections indicate that the number of persons affected by the disorder in the United States will nearly triple by the year 2050.

AD is also a major public health problem from the economic perspective. In the United States, the cost of caring for patients with AD was more than $110 billion per year in the early 1990s, and the average yearly cost per patient is about $45,000. Because methods for assessing the economic effects of neurodegenerative disorders are still in their infancy, these figures must be interpreted as underestimates.

Many excellent treatises on AD have reviewed important aspects of the disorder in considerable detail. This article is intended to be a comprehensive but not necessarily exhaustive review of AD.

Pathophysiology: The anatomic pathology of AD includes neurofibrillary tangles (NFTs); senile plaques (SPs) at the microscopic level; and cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the temporal lobe. In his original report on the disorder, Alois Alzheimer described the co-occurrence of NFTs and SPs, which is now universally accepted as a hallmark of the disease.

Although NFTs and SPs are characteristic of AD, they are not pathognomonic. In fact many other neurodegenerative conditions distinct from AD are characterized by NFTs (eg, progressive supranuclear palsy, dementia pugilistica) or SPs (eg, normal aging). Therefore, the mere presence of these lesions is not sufficient to diagnose AD. These lesions must be present in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for AD.

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer's original papers were published. These include (1) the granulovacuolar degeneration of Shimkowicz; (2) the neuropil threads of Braak et al; and (3) neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

Some authorities believed that NFTs, when present in low densities and essentially confined to the hippocampus, were part of normal aging. However, the histologic stages for AD that Braak et al formulated includes an early stage in which a low density of NFTs is present in the entorhinal and perirhinal (ie, transentorhinal) cortices. Therefore, even small numbers of NFTs in these areas of the medial temporal lobe should be considered abnormal. The issue of whether these early changes should be considered part of minimal cognitive impairment (Kuljis, 1997) or the early stages of AD instead remains to be settled experimentally.

In contrast, the presence of even low numbers of NFTs in the cerebral neocortex is considered abnormal and indicates AD if associated with SPs in that location, with a specific topographic pattern. Granulovacuolar degeneration occurs almost exclusively in the hippocampus and has received less attention than neuropil threads, which are an array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less independently of plaques and tangles. This lesion suggests neuropil alterations beyond those merely due to NFTs and SPs and indicates an even more widespread insult to the cortical circuitry than that visualized by studying only plaques and tangles.

Despite the wide distribution of these lesions in the cerebral cortex, the increasing consensus is that most patients with AD have a relatively consistent topographic pattern. NFTs are initially and most densely distributed in the medial aspect and in the pole of the temporal lobe; they affect the entorhinal cortex and the hippocampus most severely. As AD progresses, NFTs accumulate in most other cortical regions, beginning in high-order association regions and less frequently in the primary motor and sensory regions. SPs also accumulate primarily in association cortices and in the hippocampus. Plaques and tangles have relatively discrete and stereotypical patterns of laminar distribution in the cerebral cortex, which indicate predominant involvement of corticocortical connections, as many investigators have observed.

According to this formulation, the pathophysiologic mechanism underlying the clinical manifestations of AD is corticocortical disconnection due to the loss of medium-sized pyramidal neurons effecting such connections. However, multiple lines of evidence suggest that several classes of local circuit neurons are selectively lost throughout the cerebral cortex as well; these data demonstrate that the corticocortical disconnection is not the only alteration in cortical circuitry that mediates the symptoms of AD.

Frequency:
 

• In the US: The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years.

• Internationally: Prevalences similar to those in the United States have been reported in industrialized nations. Countries experiencing rapid increases in the elderly segments of their population have rates approaching those in the United States.

Mortality/Morbidity:

• Second to only certain cancers and cardiovascular disease, AD is frequently considered a leading cause of death in the United States.

• The primary cause of death is intercurrent illness, such as pneumonia, in a patient who has experienced the debilitating effects of AD for many years.

Race: Some claim that AD affects certain ethnic and racial groups more severely than others, but more study is needed before reliable statements about racial predilections can be made.

Sex: AD affects both men and women. Many studies indicate that the risk of AD is significantly higher in women than in men. Some authorities have postulated that this difference is due to the loss of the neurotrophic effect of estrogen in postmenopausal women. Other factors may also influence this relative difference.

Age: The prevalence of AD increases with age.

• AD is most prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but this represents a subgroup of the less than 10% of all familial cases of AD.

• More than 90% of cases of AD are sporadic and occur in individuals older than 60 years.

Lab Studies:
 

• Although laboratory workup should be done in any patient with a condition that can cause cognitive impairment, it is not mandatory.

• Current recommendations from the American Academy of Neurology include measurement of the cobalamin level and a thyroid function screening test. Additional investigations are left to the physician, to be tailored to the particular needs of each patient.

• Laboratory tests may include the following:

• Evaluation of the complete blood cell count and cobalamin levels: Abnormalities in these measurements require further workup to rule out hematologic disease.

• Screening of liver enzyme levels: Abnormalities in these measurements require further workup to rule out hepatic disease.

• Assessment of blood cortisol level: Abnormalities in this measurement require further workup to rule out adrenal system disease.

• Analysis of thyroid stimulating hormone (TSH) levels: Abnormalities in this measurement require further workup to rule out thyroid disease.

• Rapid plasma reagent (RPR) test: Abnormalities require further workup to rule out syphilis.

Imaging Studies:
 

• Brain MRI or CT: In assessing AD, brain MRIs or CT scans show diffuse cortical and/or cerebral atrophy. These studies are also used to rule out other CNS disease.

• SPECT: Under most circumstances, SPECT is an optional study and not considered mandatory for the routine workup of patients with typical presentations of AD. SPECT is used in qualified cases, usually those involving atypical presentations, such as language disorders (eg, progressive aphasia), visuospatial dysfunction syndromes, or other conditions that may be confused with cerebrovascular disease or other neurodegenerative conditions.

Other Tests:
 

Medical Care: Therapeutic approaches to AD are based on developing theories of its pathogenesis and on the need to alleviate its cognitive and behavioral manifestations. The predominantly symptomatic approach preceded, by many decades, the more recent interventions based on our improving understanding of the pathogenesis and pathophysiology of AD.

To date, no interventions have been shown to convincingly prevent AD or slow its progression. Medical treatments for AD include psychotropic medications and behavioral interventions, cholinesterase inhibitors (ChEIs) and the avoidance of centrally acting anticholinergic medications, N-methyl-D-aspartate (NMDA) antagonists, and other and new therapeutic interventions.

• Psychotropic medications and behavioral interventions

   

  • A variety of behavioral and pharmacologic interventions can temporarily alleviate clinical manifestations of AD, such as anxiety, agitation, depression, and psychotic behavior, which are best approached symptomatically. These interventions are useful in managing AD, though their effectiveness is often modest and temporary, and they do not prevent the eventual deterioration of the patient's condition.

     

  • Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage).

     

  • No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the US Food and Drug Administration (FDA) has not approved any agent for the treatment of AD. However, medications that many practitioners prefer are haloperidol, risperidone, olanzapine, and (more recently) quetiapine. The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients.

     

  • Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the manifestations of dementia with cortical Lewy bodies (DCLB), also known as Lewy body dementia (LBD), because patients with DCLB may be extremely sensitive to these agents. Adverse reactions to conventional neuroleptics have fueled the search for new agents that alleviate disruptive behavior while minimizing the occurrence of extrapyramidal manifestations and worsening of motor and behavioral performance, which is frequently observed in DCLB. This is the basis for the recent trend to use new-generation agents to alleviate the behavioral manifestations of AD, with therapy usually extending into the more advanced stages of the disorder.

     

  • Results of several studies indicate that anticonvulsants (eg, gabapentin) may have a role in the treatment of behavioral problems in patients with AD.

• Cholinesterase inhibitors

   

  • A strategy widely used to address the symptoms of AD is palliating the deficiency in cholinergic innervation to the cerebral cortex. Numerous lines of evidence indicate that the corticipetal cholinergic system is targeted relatively early and more or less selectively in AD. For over 2 decades, AD has been characterized by substantial loss of acetylcholine (ACh) in the cerebral cortex, progressive decline in cortical levels of choline acetyltransferase (biosynthetic enzyme necessary for the synthesis of ACh), and severe loss of neurons in the subcortical cholinergic nuclei that project to the cerebral neocortex (ie, basal nucleus of Meynert) and hippocampus (ie, medial septal nuclei).

     

  • These observations have led to the theory that some of the clinical manifestations of AD are due to loss of the cholinergic innervation to the cerebral cortex. In turn, this theory led to development of an increasing number of compounds capable of palliating the cholinergic defect by interfering with the degradation of ACh by acetylcholinesterase (AChE), the synaptic, or specific, form of cholinesterase. More recent compounds include substances capable of blocking the nonsynaptic, or nonspecific, cholinesterases; these are frequently called butyrylcholinesterases (BuChEs).

The mainstay of therapy is the use of centrally acting cholinesterase inhibitors to palliate the depletion of ACh in the cerebral cortex and hippocampus. Because the clinical manifestations of AD are believed to be partly due to a loss of the cholinergic innervation to the cerebral cortex, compounds have been developed to palliate the cholinergic defect by interfering with the degradation of ACh by AChE, the synaptic (or specific) form of cholinesterase. Some of the more recently available compounds are substances that inhibit also the nonsynaptic (or nonspecific) cholinesterases, which are frequently called BuChE.

AChE inhibitors approved by the FDA for use in the early and intermediate stages of AD are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit BuChE. This may be important for their therapeutic efficacy because BuChE levels increase during the course of AD and are present in some AD lesions, including senile plaques. At present, tacrine, is used seldom if at all because it has been superseded by the other 3. To date, the ChEIs is the only class of drugs that has been formally approved for use in AD.

An increasing number of clinical studies demonstrate that cholinesterase inhibition can have modest but detectable effects, such as improvement in cognitive performance, as measured by tools such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). More recent evidence indicates that ChEIs may also alleviate the noncognitive manifestations of AD. For example, they can ameliorate behavioral manifestations, as assessed by using tools such as the Neuropsychiatric Inventory, and they may improve the performance of activities of daily living, as evaluated by using the Progressive Deterioration Scale.

In general, the benefits are temporary because ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. Although the increasingly large family of ChEIs was originally expected to help in only the early and intermediate stages of AD, results indicate that (1) they improve cognitive performance in advanced stages; (2) they significantly improve behavioral manifestations (eg, wandering, agitation, socially inappropriate behavior associated with advanced stages); and (3) they help in patients with presumed vascular components added to dementia due to AD, as well as in patients with the DLB, which often co-occurs or overlaps with AD (Lewy body variant of AD).

Therefore, the modest benefits of ChEIs seem to extend beyond the low-level cognitive impairment in the early stages of AD. This phenomenon has not been fully explained. Interesting speculations, which remain to be tested experimentally, include the possibility that some of the newly recognized benefits in advanced behavioral and cognitive performance may be associated with the inhibition of BuChE, in addition to AChE, a characteristic of only some ChEIs currently in use.

The ChEIs share a common profile of adverse effects, the most frequent of which are nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated with slow uptitration to the desired maintenance dose. Use of drugs whose absorption peaks are blunted by food (eg, rivastigmine) can further mitigate adverse effects and improve the tolerability of ChEI treatment.

It may be reasonable to perform serial trials of different individual ChEIs when effectiveness of 1 medication decreases or if adverse effects are not tolerable. A new agent in this class should be tapered up when one switches among ChEIs, with the understanding that cognition and/or behavior may temporarily worsen during this period. No current evidence supports the use of more than 1 ChEI at a time. Another important clinical caveat is that, once a ChEI is started, it should be continued indefinitely. Stopping the medication may precipitate an acute, and possibly severe, cognitive and behavioral decline that may not be resolved by restarting the ChEI. The cause for this potentially catastrophic decline is not known.
 

Drug Category: Centrally acting AChE inhibitors -- These agents are used to palliate cholinergic deficiency.

• Patients with dementia, in general, and those with AD, in particular, usually have a progressive deterioration in their behavior, cognition, and ability to perform activities of daily living.

• These changes may result in patients making inappropriate or adverse psychosocial decisions, such as the mismanagement of funds or serious lapses in their family, social, and occupational responsibilities.

• Medical advice should include a warning about these possibilities, given to both the patient and to their caregivers (at least those most directly responsible for the patient's care) to minimize the risk of adverse legal effects on the patient or others.

• Particular attention should be given to the need to make a legal statement about the patient's competency to handle his or her affairs and about assigning power of attorney for the patient's estate and other matters. These delicate decisions must be individualized and coupled with an attorney's advice.