Originally described by Alois Alzheimer in 1907, Alzheimer's disease (AD) has emerged as the most common type of dementia in the elderly today.¹ Although the definitive diagnosis of AD requires histological confirmation, in the absence of a readily discernable cause the clinician may establish the diagnosis antemortem, with a fair degree of certainty, based on the clinical findings of a gradually progressive cognitive decline that results in the loss of memory, language skills, and activities of daily living.

As the aging population continues to grow at a vigorous pace, it becomes increasingly important to recognize the clinical spectrum of AD because of the possible benefit of medical intervention and its tremendous impact on society. The cost of caring for patients with AD in the U.S. has been estimated to be $100 billion annually and climbing.² In recent years, research studies have made major advances in our understanding of the histopathogenesis, genetic risk factors, and treatment options for this devastating neurodegenerative disease.

Epidemiology
In 1996, approximately 4 million people in the United States were clinically diagnosed with AD; this figure is expected to triple in the next 50 years.³ Women are more affected than men at a ratio of almost 2:1 due in part to the larger population of women who are over 70; however, the prevalence is still higher in women even after statistical correction for longevity.⁴ Age is another important risk factor. At the age of 60, the risk of developing AD is estimated to be 1%, doubling every five years to reach 30-50% by the age of 85.⁵ Other reported risk factors include lower levels of intelligence and education (defined as primary education only), small head size, and a family history of the disease.⁶ A recent meta analysis of head injury, as a risk factor for Alzheimer's disease, seems to establish that in males at least there is a definite association.⁷

Genetics
Genetic risk factors are clearly involved in the pathogenesis of AD. In particular, the gene for Apolipoprotein E (ApoE) on chromosome 19 has gained much recent attention. ApoE is a protein modulator of phospholipid transport that may have a role in synaptic remodeling.⁸ ApoE has three common alleles, ApoE epsilon (e) 2,3, and 4 that are expressed in varying amounts in the normal individual. It is the ApoE e4 genotype that is associated with the risk of AD. Postulated mechanisms include amyloid deposition and abnormal tau phosphorylation, a major component of neurofibrillary tangles. Unlike the chromosomal mutations that are responsible for early onset AD, the presence of ApoE in itself does not cause AD nor does it guarantee that the carrier will develop any clinical manifestations. Therefore, at this point in time it should not be used as a screening tool for normal individuals who are concerned about developing the disease.

The classic neuropathological findings in AD include amyloid plaques, neurofibrillary tangles, synaptic and neuronal cell death. Granulovacuolar degeneration in the hippocampus and amyloid deposition in blood vessels may also be seen on tissue examination, but are not required for the diagnosis (Figure 1-3).

Amyloid Plaques
Although amyloid plaques or senile plaques may be classified further according to their composition, all contain forms of ß-amyloid protein (Aß). Aß is a 39-42 amino acid peptide that is formed by the proteolytic cleavage of ß-amyloid precursor protein (APP) and is found in extracellular deposits throughout the central nervous system (CNS).⁹ Aß is thought to interfere with neuronal function due to its stimulatory effect on free radical production resulting in oxidative stress and neuronal cell death.⁶

Neurofibrillary Tangles
Neurofibrillary tangles are paired helical filaments composed of tau protein which in normal cells are essential for axonal growth and development. However, when hyper-phosphorylated, the tau protein forms tangles that are systematically deposited within neurons located in the hippocampus and medial temporal lobe, the parieto-temporal region,and the frontal association cortices leading to cell death.

Neuron and Synapse Loss
Areas of neuronal cell death and synapse loss are found throughout a similar distribution pattern as the neurofibrillary tangles, but greatly affect neurotransmitter pathways. The death of cholinergic neurons in the basalis nucleus of Meynert leads to a deficit in acetylcholine (Ach), a major transmitter thought to be involved with memory. In addition, serotonergic neurons in the median raphe and adrenergic neurons in the locus coerulus lead to deficits in serotonin and norepinephrine respectively.

Chromosomal Mutations
Genetic mutations in chromosomes 21, 14, and 1 have been shown to cause familial early-onset AD. Inherited in an autosomal dominant pattern, the chromosomal mutations account for less than 5% of all cases and result in the overproduction and deposition of Aß.¹⁰ Chromosome 21, which codes for APP, was first evaluated for an association with AD when Down's syndrome patients with the trisomy 21 aberration were observed to develop dementia in the fourth decade. Mutations in presenilin 1 (PS-1) on chromosome 14 and presenilin 2 (PS-2) on chromosome 1 also cause AD and are responsible for the majority of familial early-onset cases.

Inflammation
The exact role of inflammation in the pathogenesis of AD is still controversial. Although some studies have been able to demonstrate the presence of activated microglia (a marker of the brain's immune response) in patients with probable AD, a number of prospective clinical trials evaluating the use of drugs targeting various aspects of the immune system such as prednisone, hydroxycholoroquine, and selective COX-2 inhibitors have only been able to demonstrate marginal benefits at best.¹¹

While some studies have suggested a neuroprotective role for non-steroidal anti-inflammatory drugs¹² a recent large study of 351 patients revealed that these medications did not slow progression and cognitive decline in established mild to moderate Alzheimer's disease.¹³

AD is a progressive dementia with memory loss as the major clinical manifestation. While short-term memory impairment is often the presenting symptom, remote memory loss also appears to be affected over time. Another important feature of AD is the disturbance of language. Initially, AD patients may search for words when naming objects or while engaged in a simple conversation. But with progression of the disease, the language difficulties evolve into a communication breakdown as the patient struggles with a markedly limited vocabulary, nominal aphasia, echolalia, and defects in verbal comprehension.

Other cortical signs and symptoms such as apraxia, acalculia, and visuospatial dysfunction become apparent over the course of the disease. With the development of apraxia, patients lose the ability to carry out such simple tasks as combing their hair or turning on a water faucet. Acalculia may become evident when the patient is no longer able to maintain a checkbook or household accounts. Visuospatial abnormalities can also be seen as patients become disoriented with their body position in space.

Behavioral problems emerge throughout the various stages of the disease. Mood disturbances such as depression, anxiety, or apathy may be present early on in AD, while delusions, hallucinations, and psychosis can be prominent in later stages. In addition, aggression and inappropriate sexual behavior can be particularly problematic for the caregiver.

In advanced stages of AD, patients may exhibit extrapyramidal signs such as tremor and gait disturbance, frontal lobe release phenomena, urinary incontinence and myoclonus. Seizures can also be seen in some patients with late stage disease. Finally, patients with end-stage AD almost invariably enter a vegetative-like state as all cognitive activity ceases.

Clinical Diagnosis
In 1984 the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Diseases Association (NINCDS-ARDA) established diagnostic criteria designed for research purposes and clinical definition.¹⁴ Now recommended by the American Academy of Neurology (AAN) for the diagnosis of AD, this classification is divided into definite, probable, and possible AD.¹⁵ (See AAN national guidelines for the diagnosis and management of Alzheimer's disease, the contents of which are summarized in the following paragraphs.)

In addition to histopathological confirmation, definite AD requires the clinical finding of dementia as determined by the Mini-Mental Status Exam (MMSE) or other standardized neuropsychological testing; the exam must demonstrate deficits in two or more areas of cognition with progressive memory loss in the absence of delirium.

Probable AD is the clinical determination of dementia as described above and is supported by the findings of impaired activities of daily living, loss of specific cognitive functions such as language and motor skills, and a family history.¹⁴ Other clinical findings that support the diagnosis in patients with advanced AD are myoclonus, gait disorder, and increased muscle tone. Possible AD is considered when there is variation in the onset, presentation, or clinical course of the dementia and when a second brain disease or systemic disorder is present. Clinical factors that make the diagnosis of AD unlikely include sudden onset and focal neurological findings such as hemiparesis and visual field deficits. Clinically, both the NINCDS-ADRDA criteria and the Diagnostic and Statistical Manual of Mental Disorders IIIR definition of Dementia of the Alzheimer Type (DAT) may be used to diagnose AD with 90% accuracy.¹⁵

Differential Diagnosis
The differential diagnosis for AD is extensive and includes a multitude of neurodegenerative diseases that are associated with the development of dementia including Pick's disease, Lewy body disease, and progressive supranuclear palsy as well as other diseases such as vascular dementia and Creuztfeldt-Jakob Disease. Most of these entities can be differentiated from AD by the clinical history and a careful examination. Potentially treatable diseases that may mimic the dementia caused by AD include depression, thyroid disease, vitamin B12 deficiency, normal pressure hydrocephalus and neurosyphilis all of which should be effectively ruled out in the evaluation of AD.

Imaging Studies
In advanced cases of AD, computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate diffuse cortical atrophy with disproportionate volume loss in the medial temporal lobe structures. However, only mild atrophy and normal age-related changes may be present early on in the disease. Therefore, the utilization of imaging studies in the diagnostic workup of AD is mainly to exclude structural lesions such as subdural hemorrhage and brain tumors. Functional imaging studies used in clinical research include positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans which demonstrate hypometabolism and hypoperfusion respectively in the temporal-parietal regions bilaterally.

Laboratory Studies
Routine chemistry panels, blood counts, spinal fluid analyses and inflammatory markers are all within normal limits in patients with AD. Elecroencephalographic (EEG) recordings are usually normal or show diffuse slowing in later stages of the disease.

Management of Cognition
The major issues in treating AD are the improvement of memory and cognition and the delay of disease progression. In patients with mild to moderate disease, the mainstays of treatment are the acetylcholinesterase inhibitors, which are aimed at increasing acetylcholine levels throughout the CNS. There are now four FDA-approved drugs that have shown modest benefit over placebo and are currently available for use as outlined in Table 1. Efficacy appears to be similar among the cholinesterase inhibitors although they have not been directly compared in a clinical trial. The only reported differences are the dosing schedule and side-effect profile of each individual drug.

In addition to the use of cholinesterase inhibitors, vitamin E at 1000 I.U. BID and selegiline at 5 mg BID may also be of benefit in the pharmacologic treatment of AD.¹⁶ These antioxidant agents are thought to provide some degree of neuroprotection and in a clinical study slowed disease progression by 25% over placebo.¹⁷ However, clinical judgment needs to be carefully exercised when prescribing selegiline for AD patients as the side-effect profile of the mono-amine oxidase inhibitor may outweigh the benefit of its use. Estrogen, the acetylcholine precursor lecithin, nicotine, and muscarinic agonists have not shown any significant benefit in past clinical trials and are not approved for treatment. As mentioned before, there is currently not enough evidence yet to recommend NSAIDs for the cognitive treatment of AD, though studies are currently underway. The role of Co-Enzyme Q10 in the management of early AD awaits further study.

Management of Non-cognitive Symptoms
Depression is common in patients with AD and may require pharmacologic treatment. Serotonin reuptake inhibitors are relatively well tolerated by patients and are preferred over tricyclic antidepressants, which can often exacerbate the cognitive impairment due to its anticholinergic properties. The occurrence of behavioral disturbances such as psychosis and agitation requires an investigation for a correctable underlying cause such as a urinary tract infection before a neuroleptic agent should be considered. If there is no external etiology, then the establishment of a quiet, controlled, and familiar environment for the patient can help to decrease confusion and disorientation.

Behavioral disturbances in AD may also be treated pharmacologically with both traditional and atypical neuroleptics. Although haloperidol can be effective, the atypical anti-psychotics, which include risperidone, quetiapine, and olanzepine, may be better tolerated than traditional agents. There is not enough evidence to support the use of benzodiazepines, lithium, and anticonvulsants for the treatment of psychosis in patients with AD.¹⁶

Special care units within long-term care facilities may be considered as some studies have shown a reduced need for anti-psychotics and physical restraints as well as a decrease in behavioral disturbances in AD patients who reside there.¹⁶ Finally, psychosocial intervention for the caregiver is an integral part of managing patients with AD. Education, support groups, and respite care services are invaluable to family members and friends who provide the primary care for AD patients.¹⁸

The Future
A number of novel approaches are being studied in the hope that one or more may prevent, or even reverse the accumulation of the toxic substance beta amyloid alluded to earlier. These include vaccination to remove amyloid build up as well as manipulation of enzyme systems referred to as secretases.

With the number of AD patients expected to grow exponentially over the next few decades, further studies are needed to elucidate our understanding of the disease, its risk factors, and potential treatments. This is critical not only for those at risk who can be identified in the pre-clinical state for early intervention, but also for the patients and their caregivers whose lives are forever changed by the tragedy of this disease.

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