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Snapshot
  • A 78-year-old man presents to his primary care clinic and is accompanied by his wife. He feels well, but his wife is concerned that he has become more confused over the past few weeks. He enjoys socializing with family and friends, but sometimes has difficulty finding words and recently forgot his niece's name. He walks around his neighborhood for exercise, but has the tendency to wander and get lost. He has a history of hypertension and atrial fibrillation. Current medications are warfarin and dronedarone. Physical exam is unremarkable. Recent lab results were within normal limits. 
Introduction
  • Most common cause of dementia in the elderly
  • Pathogenesis remains unclear, but involves
    • accumulation of neurotoxic proteins, amyloid beta (Aβ-amyloid) and tau
    • ↓ ACh neurotransmission by cholinergic neurons in the nucleus basalis of Meynert 
Causes
  • Majority are sporadic
  • Genetic forms
    • early-onset
      • rare
      • autosomal dominant
      • can involve presenilin mutations 
        • presenilin-1 (chromosome 14)
        • presenilin-2 (chromosome 1)
      • associated with Down syndrome (trisomy 21)
        • ↑ risk of developing Alzheimer's because APP gene is located on chromosome 21  
        • commonly presents before age 40 
    • late-onset 
      • allele variations of apolipoprotein E (APOE) on chromosome 19 affect risk of developing Alzheimer's disease 
        • ε4 is associated with increased risk
        • ε2 is associated with decreased risk
Presentation
  • Progressive symptoms
    • mild
      • short-term memory loss
    • moderate 
      • inability to learn/recall information
      • long-term memory loss
      • wandering
      • mood swings and personality changes including aggression
    • severe
      • incontinence
      • gait disturbance
      • unable to perform ADLs
Evaluation
  • Clinical diagnosis of exclusion
    • confirmation is autopsy histology
  • Characteristic findings on histopathology (see above image):
    • senile/neuritic plaques
      • extracellular Aβ-amyloid core derived from amyloid precursor protein (APP) 
        • APP normally degraded via α-cleavage
        • β-cleavage of APP results in Aβ-amyloid
    • neurofibrillary tangles
      • intracellular aggregations of hyperphosphorylated tau protein
        • tau is an insoluble cytoskeletal element (microtubule-associated protein)
      • tangles correlate with degree of dementia
    • neuronal degeneration
      • results in diffuse cortical atrophy
      • widening of sulci, narrowing of gyri, expansion of the ventricles
Treatment
  • See Alzheimer's drugs
Prognosis, Prevention, and Complications
  • Complications
    • amyloidosis may result in angiopathy
    • results in weakened vessel walls and can lead to rupture with intracranial hemorrhage
  • Most common cause of death is infection
    • mental status changes associated with sepsis are not detected when superimposed on baseline Alzheimer's disease
 

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