Alzheimer Disease

Snapshot

• A 78-year-old man presents to his primary care clinic with his wife. He feels well, but his wife is concerned that he has been forgetful. She noticed he had trouble with remembering things over the course of the year. She says that he has been getting lost recently when he goes to the local grocery store. She has noticed that he has become more irritable. He would frequently forget things that were recently told him. Physical examination and laboratory studies are normal. Montreal Cognitive Assessment is 22 out of 30.

Introduction

• Definition
  • a neurodegenerative disorder that is characterized by
    • cognitive decline
      • e.g., dementia
    • difficulty completing activities of daily living
      • e.g., balancing a checkbook, buying groceries, and cooking
    • psychiatric and behavioral issues
• Epidemiology
  • incidence
    • the most common cause of dementia
  • risk factors
    • increasing age
    • trisomy 21
      • due to amyloid precursor protein being found in chromosome 21  
• Etiology
  • sporadic (in 95% of cases)
  • apolipoprotein E (APOE) genotype 
    • APOE4 is associated with an increased risk of developing Alzheimer disease (AD) 
      • Late-onset (>60 years)
    • APOE2 is protective against AD
  • presenilin-1 (chromosome 14) and presenilin-2 (chromosome 1) 
    • associated with early-onset AD 
    • onset before age 60
• Pathogenesis
  • the cause is unclear; however, histopathology demonstrates
    • extracellular amyloid plaques
    • intraneuronal neurofibrillary tangles  
    • altered nucleus basalis of Meynert (a cholinergic nucleus) 
      • prominently affected 
  • gross pathology
    • hippocampal and temporal lobe atrophy
    • hydrocephalus ex vacuo
• Associated conditions
  • decreased acetylcholine
• Down syndrome

Presentation

• Symptoms 
  • impaired declarative episodic memory
    • this is a memory of events that occurred in a specific time and place
  • impaired ability to remember new pieces of information
  • visuospatial and language deficits
  • behavioral and psychological impairment
    • apathy
    • social isolation
• irritability

Imaging

• MRI brain
  • findings
• may demonstrate volume loss in the hippocampus and temporal lobe

Studies

• Clinical diagnosis
  • rule out reversible causes of dementia (e.g., vitamin B12 deficiency and hypothyroidism)
  • cognitive testing
    • Montreal Cognitive Assessment
• mini mental status exam

Differential

• Normal pressure hydrocephalus
  • differentiating factor
    • dementia (wide-based), gait instability, and urinary incontinence
      • diagnosed with improvement of gait after a lumbar puncture
      • managed by a ventriculoperitoneal shunt
• Vascular dementia
  • differentiating factor
    • a step-wise cognitive decline in the setting of recent stroke significant vascular brain injury on brain imaging
• Creutzfeldt-Jakob disease
  • differentiating factors
    • rapidly progressive dementia with startle myoclonus 
    • presence of 14-3-3 protein in the cerebral spinal fluid
• Normal aging
  • differentiating factors
    • preservation of procedural, primary, and semantic memory
    • decreased episodic and working memory
    • decreased executive function
• Dementia with Lewy bodies
  • differentiating factors
    • visual hallucinations
    • fluctuating cognition
    • parkinsonism
    • REM sleep disorder
    • neuroleptic sensitivity
• Frontotemporal dementia
  • differentiating factors
    • disinhibition and apathy (in the behavioral variant)
• aphasia (in the primary progressive aphasia variant)

Treatment

• Medical
  • cholinesterase inhibitors
    • indication
      • increases cortical cholinergic function and typically used in mild-moderate AD
        • recall that this disease is associated with decreased cortical acetycholine
    • medications
      • donepezil
      • rivastigmine
      • galantamine
  • memantine
    • indication
      • neuroprotective N-methyl-D-aspartate (NMDA) receptor antagonist typically used in moderate-severe Alzheimer disease
• believed that neuronal excitotoxicity plays a role in the development of AD

Complications

• Difficulty with eating or refusal to eat
• Infection