Alzheimer Disease

David S. Knopman, MD
Mayo Clinic

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition

• The most common dementia in which the dominant initial symptom is short-term memory impairment
• Slowly progressive disorder that eventually evolves into a pervasive loss of most domains of intellectual function

Key Clinical Features

• Typically becomes symptomatic with complaints of forgetfulness and confusion
• Progressive worsening of the following:
  • Short-term memory (specifically, an inability to learn new information)
  • Language
  • Visuospatial processing
  • Abstract reasoning and executive functioning
• Associated symptoms
  • Apathy and loss of initiative
  • Depression
  • Incontinence (in advanced disease)
  • Hallucinations and delusions (most often after initial stages)
  • Verbal and physical aggressiveness

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Differential Diagnosis

• Subacute delirium caused by drug intoxications
• Major depression
• Metabolic disorders
  • Hypothyroidism
  • Vitamin B₁₂ deficiency
  • Thiamine deficiency
  • Liver or renal failure
• Space-occupying lesions
• Vascular dementia
• Dementia with Lewy bodies
• Frontotemporal lobar degenerations

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Best Tests

• Thorough history
• General physical exam
• Neurologic exam
• Mental status examination
• Laboratory tests used primarily to rule out other conditions, though biomarkers are currently being developed
• MRI
  • Good sensitivity but does not add to sensitivity of clinical diagnosis
  • Excellent for ruling out other conditions, including space-occupying lesions and cerebral infarcts
  • Hippocampal atrophy has best sensitivity and specificity
• CT
  • Poor sensitivity
  • Useful to eliminate space-occupying lesions such as subdural hematomas or brain tumors that present as subacute dementia
  • Most cost-effective for eliminating other disorders but not adequate to evaluate for coexistent cerebral infarcts
• Lumbar puncture
  • Good sensitivity for biomarkers tau, abeta, and ADC7, but these do not add to sensitivity of clinical diagnosis
  • Useful for eliminating CNS infections or meningeal cancer that could present as subacute dementia
  • Routine CSF unremarkable
• EEG
  • No value for diagnosis
  • Useful for eliminating seizures as a cause of cognitive impairment
  • Normal pattern or nonspecific changes
• Genotyping
  • Good sensitivity for APOE but does not add to sensitivity of clinical diagnosis
  • Specificity of APOE genotype good but not sufficiently specific
  • APOE genotyping is commercially available.
  • Genotyping for APP, PS1, and PS2 mutations should be limited to young-onset cases with strong family history of early onset

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Best Therapy

• Currently available agents are palliative but may have clinically valuable benefits for some patients by delaying progression of symptoms of cognitive loss
• No proven preventive therapies
• No agents consistently effective in preventing progression
• Avoid drugs with anticholinergic effects
• Coping strategies and education regarding genetic susceptibility important for patient and family

Cholinesterase Inhibitors

• Donepezil
  • Once-a-day dosing
  • Efficacy equivalent to others
  • Dose: 5–10 mg/day
  • Cost/mo (maximum dose): $127.99
• Galantamine
  • Twice-a-day dosing
  • Efficacy equivalent to others
  • Dose: 8–24 mg/day
  • Cost/mo (maximum dose): $131.98
• Rivastigmine
  • Twice-a-day dosing
  • Efficacy equivalent to others
  • Dose: 3–12 mg/day
  • Cost/mo (maximum dose): $133.98

NMDA Receptor Antagonists

• Memantine
  • Twice-a-day dosing
  • Efficacy compared with cholinesterase inhibitors: from comparable to somewhat less effective
  • Dose: 20 mg/day; start at 5 mg, titrate at 5 mg/wk
  • Cost/mo: $136.36

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Best References

Doody, et al: Neurology 56:1154, 2001

Knopman, et al: Neurology 56:1143, 2001

Petersen, et al: Neurology 56:1133, 2001

Small, et al: JAMA 278:1363, 1997

July 2005