Alzheimer Disease Overview

Alzheimer's Disease Pathophysiology

• Proposed mechanisms for AD changes include:
  • β amyloid protein aggregation, leading to formation of plaques
  • Hyperphosphorylation of tau protein, leading to neurofibrillary tangles (NFTs)
  • Synaptic failure and depletion of neurotrophin and neurotransmitters
  • Mitochondrial dysfunction
  • Oxidative stress

Amyloid Cascade Hypothesis

• Involves a β-amyloid production and clearance imbalance, leading to AD
• Aggregation and accumulation of β-amyloid leads to AD

Neurotransmitter Deficits

• Loss of cholinergic activity is the most prominent neurotransmitter deficit that correlates with AD severity
• Cholinergic cell loss is a consequence of AD pathology, not the cause
• Other neurotransmitters involved include:
  • Serotonergic neurons of the raphe nuclei and noradrenergic cells of the locus ceruleus are lost
  • Monoamine oxidase type B activity is increased
  • Glutamate pathways of the cortex and limbic structures are abnormal
  • Excitatory neurotransmitters, including glutamate, may be neurotoxic

Clinical Presentation

• Early disease may be characterized by changes in:
  • Learning and memory
  • Planning and organization
  • Mood
• As the disease progresses, further declines in these domains, as well as changes in:
  • Personality
  • Judgment
  • Speech
  • Spatial orientation
• In the late stages, functional decline may result in:
  • Gait disturbances
  • Swallowing difficulties
  • Incontinence symptoms
  • Behavioral changes
• Patients become increasingly unable to care for themselves

Alzheimer's Disease Introduction

• Affects approximately 7.5 million Americans of all ages
• Progressive illness of unknown cause
• Characterized by loss of cognitive and physical functioning, commonly with behavioral symptoms

Risk Factors

• Genetic susceptibility to late-onset AD is primarily linked to the apolipoprotein E (APOE) genotype
• AD occurrence at a young age is seen in less than 1% of cases
• Risk factors include:
  • Age
  • Decreased brain reserve capacity
  • Head injury
  • Down syndrome
  • Depression
  • Mild cognitive impairment
  • Risk factors for vascular disease, including:
    • Hypertension
    • Elevated homocysteine
    • Elevated low-density lipoprotein cholesterol
    • Low high-density lipoprotein cholesterol
    • Obesity
    • Metabolic syndrome
    • Diabetes

Signature Lesions

• Intracellular neurofibrillary tangles (NFTs)
• Extracellular plaques in the cortex and medial temporal lobe
• Degeneration of neurons and synapses
• Cortical atrophy
• AD affected individuals appear to have a higher burden of plaques and NFTs in their younger years compared to age-matched controls