Neurology

Alzheimer's Disease

Jinny Tavee

Patrick Sweeney

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Definition

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 histologic confirmation, in the absence of a readily discernible 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, activities of daily living, and executive function.

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 United States 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.

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Prevalence

Epidemiology

In 1996, AD was clinically diagnosed in approximately 4 million people in the United States; 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, partly because of the larger population of women who are older than 70 years; 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 years, the risk of developing AD is estimated to be 1%, doubling every 5 years to reach 30% to 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 meta-analysis of head injury as a risk factor for Alzheimer's disease also demonstrated a definite association in men.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 might have a role in synaptic remodeling.8 ApoE has three common alleles, ApoE ε2, ε3, and ε4, which are expressed in varying amounts in the normal person. It is the ApoE ε4 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 time it should not be used as a screening tool for normal patients who are concerned about developing the disease.

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Pathophysiology

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

Amyloid Plaques

Although amyloid plaques or senile plaques may be classified further according to their composition, all contain forms of β-amyloid protein (Aβ). Aβ is a 39- to 42-amino acid peptide that is formed by the proteolytic cleavage of β-amyloid precursor protein (APP) and is found in extracellular deposits throughout the central nervous system (CNS).9 Aβ is believed to interfere with neuronal activity because of its stimulatory effect on production of free radicals, 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 is essential for axonal growth and development. However, when hyperphosphorylated, the tau protein forms tangles that are deposited within neurons located in the hippocampus and medial temporal lobe, the parietotemporal 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 distribution pattern similar to that of the neurofibrillary tangles, but they 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 believed to be involved with memory. In addition, loss of serotoninergic neurons in the median raphe and adrenergic neurons in the locus ceruleus 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 Aβ.10 Chromosome 21, which codes for APP, was first evaluated for an association with AD when Down 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, hydroxychloroquine, and selective COX-2 inhibitors have been able to demonstrate only marginal benefits at best.11

Although some studies have suggested a neuroprotective role for nonsteroidal anti-inflammatory drugs, 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.12,13

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Signs and symptoms

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

Other cortical signs and symptoms such as apraxia, acalculia, and visuospatial dysfunction may 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 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, whereas 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 might 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. Patients with end-stage AD almost invariably enter a vegetative state when all cognitive activity ceases.

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Diagnosis

Clinical Diagnosis

In 1984, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Diseases Association (NINCDS-ADRDA) 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 the 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 histopathologic confirmation, definite AD requires the clinical finding of dementia as determined by the Mini-Mental State Examination (MMSE) or other standardized neuropsychological testing; the examination 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 just described 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 neurologic 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 other diseases such as vascular dementia and Creutzfeldt-Jakob disease. Most of these entities can be differentiated from AD by the clinical history and a careful examination. Potentially treatable diseases that can 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 use 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. Amyloid burden imaging compounds are under development (Pittsburgh Compound B).

Laboratory Studies

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

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Treatment

Management of Cognition

The major issues in treating AD are the improvement of memory and cognition and the delay of disease progression. At present there are no proven medications that cure or slow progression in Alzheimer's disease. Temporary improvements in cognition and behavior can be seen with the two existing drug classes of cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists.

The three cholinesterase inhibitors as well as the NMDA receptor antagonist memantine are listed in Box 1. The new patch formulation of rivastigmine (Exelon) allows the convenience of once-daily administration, with a marked decrease in the common gastrointestinal (GI) side effects seen with the cholinesterase inhibitors. Efficacy appears to be similar among the cholinesterase inhibitors. The only reported differences are the dosing schedule and side-effect profile of each individual drug.

Box 1: Drug Therapy for Alzheimer's Disease
Acetylcholinesterase Inhibitors
  • Donepezil
    • 5 mg once daily, can increase to 10 mg daily after 4-6 wk
  • Rivastigmine tartrate
    • Pill: 1.5 mg bid initially, then titrate by 1.5 mg bid every 2 wk up to 12 mg daily
    • Patch: 4.6 and 9.5 mg patch size daily
  • Galantamine*
    • 4 mg bid initially, then titrate by 4 mg bid every 4 wk up to 24 mg daily
  • Galantamine ER
    • 8 mg daily, the titrate by 8 mg/d every 4 wk up to 24 mg daily
NMDA Receptor Antagonists
  • Memantine (Namenda)
    • 10 mg bid

*Renal and hepatic dose adjustments are required.
NMDA, N-methyl-d-aspartate.


The second drug class widely used in the treatment of Alzheimer's disease recognizes the increasing role of glutamate overstimulation of NMDA receptors on the surface of neurons. It is believed that this results in long-term excessive calcium influx into the neuron through the NMDA surface channel. By inhibiting this excessive influx, some improvements in cognition and behavior have been demonstrated in severe Alzheimer's disease.

An evidence review of the effectiveness of these drugs in the treatment of dementia concluded that “they can result in statistically significant but clinically marginal improvements in the measures of cognition and global assessment of dementia.”16

Management of Noncognitive Symptoms

Depression is common in patients with AD and can require pharmacologic treatment. Serotonin reuptake inhibitors are relatively well tolerated by patients and are preferred over tricyclic antidepressants, which often exacerbate the cognitive impairment as a result of their anticholinergic properties. Behavioral disturbances such as psychosis and agitation require 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 establishing 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 antipsychotics, which include risperidone, quetiapine, and olanzapine, 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.17

Special care units within long-term care facilities are another consideration; some studies have shown a reduced need for antipsychotics and physical restraints as well as a decrease in behavioral disturbances in AD patients who reside there.17 Psychosocial intervention for the caregiver is also an integral part of managing patients with AD. Education, support groups, and respite care services are should be suggested 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 might prevent or even reverse the accumulation of the toxic substance β-amyloid discussed earlier. These include the development of vaccines to remove or prevent amyloid accumulation and the manipulation of enzyme systems referred to as secretases. Unfortunately, the Ginkgo Evaluation of Memory (GEM) study showed that Gingko biloba extract, when taken by normal patients older than 85 years, failed to alter the risk of progression from normal to Clinical Dementia Rating (CDR) stage 0.5 and had no beneficial effect in preserving memory function.19

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Outcomes

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 preclinical 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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Summary

  • Worldwide estimates of dementia prevalence increase from 24 million today to 81 million in 2040.
  • Increasing age is the most powerful nonmodifiable risk factor.
  • Potentially treatable causes of cognitive decline need to be excluded before establishing the diagnosis of AD.
  • Current drug therapy offers mild benefit.

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References

  1. Alzheimer A. Über eine eigenartige Erkangkung der Hirnrinde. Allgemeine Zeitschr Psychisch-Gerichtliche Medizin. 1907, 64: 146-148. English translation available in Arch Neurol 1967;21:109-110.
  2. Ernst R, Hay J. The US economic and social costs of Alzheimer's disease revisited. Am J Public Health. 1994, 84: 1261-1264.
  3. Geldmacher DS, Whitehouse PJ. Differential diagnosis of Alzheimer's disease. Neurology. 1997, 48: (S6): S2-S9.
  4. Canadian Study of Health and Aging Working Group. Canadian study of health and aging: Study methods and prevalence of dementia. Can Med Assoc J. 1994, 150: 899-913.
  5. Graves AB, Kukull WA. The epidemiology of dementia. Morris JC(ed): Handbook of Dementing Illneses. New York: Marcel Dekker, 1994, pp 23-69.
  6. Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology. 1998, 51: (suppl 1): S2-S17.
  7. Fleminger S, Oliver DL, Lovestone S, et al: Head injury as a risk factor for Alzheimer's disease: The evidence ten years on. J Neurol Neurosurg Psychiatry. 2003, 74: 857-862.
  8. Poirer J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci. 1994, 17: 525-530.
  9. Swartz RH, Black SE, St George-Hyslop P. Apolipoprotein E and Alzheimer's disease: A genetic, molecular, and neuroimaging review. Can J Neurol Sci. 1999, 26: 77-88.
  10. Bird TD. Clinical genetics of familial Alzheimer's disease. In: Terry RD, Katzman R, Bick KL (eds): Alzheimer Disease. New York: Raven Press, 1994, pp 65-74.
  11. Jones RW. Inflammation and Alzheimer's disease. Lancet. 2001, 358: 436-437.
  12. Veld BA, Ruitenberg A, Hofman A, et al: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001, 345: 1515-1521.
  13. Aisen PS, Schafer KA, Grundman M, et al: Effects of rofecoxib or naproxen vs placebo on Alzheimer's disease progression. JAMA. 2003, 289: 2819-2826.
  14. McKhann G, Drachman DD, Folstein M, et al: Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984, 34: 939-944.
  15. Knopman DS, DeKosky ST, Cummings JL, et al: Practice parameter: Diagnosis of dementia (an evidence based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001, 56: 1143-1153.
  16. Doody RS, Stevens JC, Beck C, et al: Practice parameter: Management of dementia (an evidence based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001, 56: 1154-1166.
  17. Sano M, Ernesto C, Thomas RG, et al: A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer's disease. N Eng J Med. 1997, 336: 1216-1222.
  18. Haley WE. The family's caregiver role in Alzheimer's disease. Neurology. 1997, 48: (suppl 6): S25-S29.

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Suggested Readings

  • Aisen PS, Schafer KA, Grundman M, et al: Effects of rofecoxib or naproxen vs. placebo on Alzheimer's disease progression. JAMA. 2003, 289: 2819-2826.
  • Alzheimer A. Über eine eigenartige Erkangkung der Hirnrinde. Allgemeine Zeitschr Psychisch-Gerichtliche Medizin. 1907, 64: 146-148. English translation available in Arch Neurol 1967;21:109-110.
  • Bird TD. Clinical genetics of familial Alzheimer's disease. In: Terry RD, Katzman R, Bick KL (eds): Alzheimer Disease. New York: Raven, 1994, pp 65-74.
  • Canadian Study of Health and Aging Working Group. Canadian study of health and aging: Study methods and prevalence of dementia. Can Med Assoc J. 1994, 150: 899-913.
  • Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology. 1998, 51: (S1): S2-S17.
  • Dodge H, Zitzleberg T, Oken B, Howieson D, Kaye J. A randomized placebo-controlled trial of ginkgo biloba for the prevention of cognitive decline. Neurology. 2008, 70: 1809-1817.
  • Doody RS, Stevens JC, Beck C, et al: Practice parameter: Management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001, 56: 1154-1166.
  • Ernst R, Hay J. The US economic and social costs of Alzheimer's disease revisited. Am J Public Health. 1994, 84: 1261-1264.
  • Fleminger S, Oliver DL, Lovestone S, et al: Head injury as a risk factor for Alzheimer's disease: The evidence ten years on. J Neurol Neurosurg Psychiatry. 2003, 74: 857-862.
  • Geldmacher DS. Whitehouse PJ. Differential diagnosis of Alzheimer's disease. Neurology. 1997, 48: (S6): S2-S9.
  • Graves AB, Kukull WA. The Epidemiology of Dementia. Morris JC(ed): Handbook of Dementing Illneses. New York: Marcel Dekker, 1994, pp 23-69.
  • Haley WE. The family's caregiver role in Alzheimer's disease. Neurology. 1997, 48: (S6): S25-S29.
  • Jones RW. Inflammation and Alzheimer's disease. Lancet. 2001, 358: 436-437.
  • Knopman DS, DeKosky ST, Cummings JL, et al: Practice parameter: Diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001, 56: 1143-1153.
  • McKhann G, Drachman DD, Folstein M, et al: Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984, 34: 939-944.
  • Poirer J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci. 1994, 17: 525-530.
  • Raina P, Santaguida P, Ismaila A, et al: Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008, 148: 379-397.
  • Sano M, Ernesto C, Thomas RG, et al: A controlled trial of selegiline, α tocopherol, or both as treatment for Alzheimer's disease. N Eng J Med. 1997, 336: 1216-1222.
  • Swartz RH, Black SE, St. George-Hyslop P. Apolipoprotein E and Alzheimer's disease: A genetic, molecular, and neuroimaging review. Can J Neurol Sci. 1999, 26: 77-88.
  • Veld BA, Ruitenberg A, Hofman A, et al: Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001, 345: 1515-1521.