Alzheimer's disease pathology

Alzheimer's disease pathology

Alzheimer's disease pathology

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Gross Pathology - Shrinking Brain Blues

Normal vs. Alzheimer's Brain: Gross and Sectional Views

  • Generalized cortical atrophy: The brain shrinks, leading to:
    • Widened sulci: The grooves on the brain's surface become broader.
    • Narrowed gyri: The folds of the brain become thinner.
  • Hydrocephalus ex vacuo: Compensatory enlargement of ventricles as brain parenchyma is lost. CSF pressure remains normal.
  • Hippocampal atrophy: Severe shrinkage of the hippocampus is a key feature.

⭐ Hippocampal atrophy is a key early finding on MRI, correlating with the severity of memory loss.

Extracellular Pathology - Plaque Attack

  • Senile (neuritic) plaques are extracellular aggregates of Amyloid-β (Aβ) peptides, primarily the toxic Aβ42 fragment, formed by enzymatic cleavage of Amyloid Precursor Protein (APP).
  • Staining: Visualized with Congo Red (apple-green birefringence) and Thioflavin-S.
  • Cerebral Amyloid Angiopathy (CAA): Aβ deposition in vessel walls, increasing hemorrhage risk.

⭐ Aβ42's hydrophobic nature makes it highly prone to aggregation, initiating plaque formation.

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Intracellular Pathology - Tangled Tau

  • Normal Function: Tau protein is an intracellular microtubule-associated protein (MAP) that provides structural stability to neuronal axons, acting like railway ties for axonal transport.
  • Pathology: In Alzheimer's disease, Tau becomes pathologically hyperphosphorylated.
    • This causes Tau to detach from microtubules, leading to their destabilization and disintegration.
    • The abnormal Tau protein misfolds and aggregates into insoluble Paired Helical Filaments (PHFs).
  • Result - NFTs: These PHFs accumulate within the neuron to form Neurofibrillary Tangles (NFTs).
    • Appearance: NFTs have a classic intracytoplasmic, "flame-shaped" appearance in pyramidal neurons.
    • Staining: Visualized with silver stains (Bielschowsky, Gallyas) and immunohistochemistry for Tau.

Alzheimer's pathology: plaques, tangles, and protein stains

High-Yield: Tangle density and distribution (measured by Braak staging) correlate much more strongly with the severity of cognitive decline in Alzheimer's disease than amyloid plaque load.

Genetic Factors - The Gene Scene

Onset TypeKey Genes & LociNotes
Late-Onset (>95%)ApoE4 allele on Chr 19↑ Risk for sporadic AD
(Sporadic)ApoE2 allele on Chr 19↓ Protective
Early-Onset (<5%)APP on Chr 21Amyloid Precursor Protein
(Familial)PSEN1 on Chr 14Presenilin 1 (most common)
PSEN2 on Chr 1Presenilin 2

⭐ The ApoE4 allele is the strongest genetic risk factor for late-onset AD.

High‑Yield Points - ⚡ Biggest Takeaways

  • Core pathology involves extracellular Aβ-amyloid plaques (derived from APP) and intracellular neurofibrillary tangles of hyperphosphorylated tau.
  • Gross anatomy shows diffuse cortical atrophy, most prominent in the hippocampus and temporoparietal lobes.
  • Cerebral amyloid angiopathy (CAA) is a frequent co-pathology, elevating the risk of lobar hemorrhage.
  • ApoE4 allele is the most significant genetic risk factor for late-onset AD.
  • Early-onset familial AD is linked to mutations in APP, PSEN1, and PSEN2.

Practice Questions: Alzheimer's disease pathology

Test your understanding with these related questions

A 70-year-old man with a long-standing history of diabetes mellitus type 2 and hypertension presents with complaints of constant wrist and shoulder pain. Currently, the patient undergoes hemodialysis 2 to 3 times a week and is on the transplant list for a kidney. The patient denies any recent traumas. Which of the following proteins is likely to be increased in his plasma, causing the patient’s late complaints?

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Flashcards: Alzheimer's disease pathology

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Alzheimer disease is characterized by _____ of sulci

TAP TO REVEAL ANSWER

Alzheimer disease is characterized by _____ of sulci

widening

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