Updated: 2/4/2021

Alzheimer Disease

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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
    • 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

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(M1.NE.14.72) A 38-year-old man with mental retardation (IQ 50), facial features that include epicanthic folds and low-set small ears, and hands pictured in Figure A, is brought in by his elderly parents, who provide constant care. They are concerned that over the past 3 years, he has become increasingly forgetful and less interested in conversing and sharing his thoughts. If a post-mortem brain autopsy were conducted, the most likely histopathological feature in his brain underlying these changes would be:

QID: 106502
FIGURES:
1

Beta-amyloid plaques and neurofibrillary tangles of phosphorylated tau

65%

(153/237)

2

Clumps of alpha-synuclein and ubiquitin protein in neurons

5%

(11/237)

3

Multiple, scattered ischemic lesions in the cortex

5%

(12/237)

4

Marked loss of cells in the head of caudate with dilated lateral ventricles

11%

(25/237)

5

Many round vacuoles in the gray matter consistent with spongiform changes

8%

(18/237)

M 1 D

Select Answer to see Preferred Response

(M1.NE.13.74) A 40-year-old man with Down syndrome is brought to your clinic by his mother. She reports that over the past few months he has started having difficulty managing his daily routine at his assisted-living facility and no longer seems like himself. She says that last week he wandered away from the facility and was brought back by police. Additionally, he has stopped taking his regular antiepileptic medication, and she is concerned that he might have a seizure. TSH is checked and is normal. Which of the following is most likely to be responsible for this man's current presentation?

QID: 100590
1

Expansion of trinucleotide repeats

10%

(13/129)

2

Abnormal protein accumulation

55%

(71/129)

3

Hormone deficiency

3%

(4/129)

4

Premature degradation of a protein

26%

(33/129)

5

Nutritional deficiency

5%

(6/129)

M 1 E

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Evidence (5)
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EXPERT COMMENTS (6)
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