Alzheimer’s Disease (AD)

Definition

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and characteristic neuropathological hallmarks, including amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau.

Symptoms

  • Progressive memory impairment (episodic memory typically affected first).
  • Cognitive decline in executive function, language, and visuospatial skills.
  • Behavioral and psychological symptoms (apathy, depression, irritability).
  • In late stages, significant loss of motor function and independence.

Mechanisms

  • Amyloid Cascade Hypothesis: Accumulation of Aβ plaques as a primary driver. (First proposed by Hardy & Higgins, 1992)
  • Tau Tangles: Formation of neurofibrillary tangles correlating strongly with cognitive decline.
  • Calcium Homeostasis Dysregulation: Aβ-induced calcium influx as a link to tau pathology.
  • Neuroinflammation: Chronic activation of microglia and astrocytes. (See: Microglia-T cell Interaction)
  • Cell-Type-Specific Genetic Risk: Recent causal modeling (Yang et al., 2023) indicates that:
    • Astrocytic risk primarily drives early Aβ accumulation.
    • Microglial risk drives both Aβ and tau pathologies, as well as cognitive decline.

Large-scale biobank studies (Levine et al., 2023) have identified significant associations between viral exposures and AD risk:

  • Viral encephalitis: Strongest association (Hazard Ratio > 20 in some cohorts).
  • Influenza and Varicella-zoster: Also linked to increased risk.
  • Hypothesis: Viral infections may prime the brain’s immune system or directly trigger neurodegenerative processes. (See: Viral Links to Neurodegeneration)