What are the types of cerebral amyloid angiopathy (CAA)?

Types of Cerebral Amyloid Angiopathy (CAA)

Cerebral amyloid angiopathy (CAA) is classified into several distinct types based on the specific amyloid protein deposited in the cerebrovascular walls, with sporadic Aβ-type CAA being the most common form in older individuals.

Primary Classification of CAA Types

Based on Amyloid Protein Type:

1. Aβ-type CAA (most common)

   • Sporadic Aβ-type CAA

     • Typically affects elderly individuals
     • Associated with aging and Alzheimer's disease
     • ApoE ε4 allele is a significant risk factor 1

   • Hereditary/Familial Aβ-type CAA

     • Associated with mutations in:
       • APP (Amyloid Precursor Protein) gene - missense mutations and copy number variants
       • PSEN1 and PSEN2 (Presenilin) genes 2
     • Examples include Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch type 3

2. Non-Aβ CAA types (less common, hereditary forms)

   • Cystatin C-related CAA

     • Hereditary Cerebral Hemorrhage with Amyloidosis-Icelandic type (HCHWA-I)
     • Caused by mutations in the CST3 gene 2, 3

   • Transthyretin (TTR)-related CAA

     • Associated with TTR gene mutations 2, 4

   • Gelsolin-related CAA

     • Caused by mutations in the GSN gene 2, 3

   • Prion protein-related CAA

     • Associated with PRNP gene mutations 2, 3

   • BRI2 gene-related CAA

     • Found in Familial British Dementia and Familial Danish Dementia
     • Associated with mutations in the ITM2B gene (formerly BRI2) 2, 3

Morphological Classification of Sporadic Aβ-type CAA:

1. CAA-Type 1

   • Characterized by Aβ deposition in:
     • Cortical capillaries
     • Leptomeningeal and cortical arteries
     • Arterioles, veins, and venules
   • Strongly associated with ApoE ε4 allele (4x higher frequency)
   • Features capillary involvement ("dyshoric angiopathy") 5

2. CAA-Type 2

   • Aβ deposition in:
     • Leptomeningeal and cortical vessels
     • Notably spares cortical capillaries
   • Higher frequency of ApoE ε2 allele
   • Does not involve capillaries 5

Clinical Significance and Complications

CAA can lead to several serious complications:

1. Hemorrhagic lesions

   • Lobar intracerebral macrohemorrhage
   • Cortical microhemorrhage
   • Cortical superficial siderosis/focal convexity subarachnoid hemorrhage 4

2. Ischemic lesions

   • Cortical infarction
   • White matter ischemic changes 4

3. Inflammatory manifestations

   • CAA-related inflammation/angiitis
   • Subacute leukoencephalopathy 1, 4

4. Cognitive impairment and dementia

   • Often coexists with Alzheimer's disease pathology 6

Special Considerations

• Early-onset CAA requires specific investigation for genetic causes or rare acquired forms, including iatrogenic subtypes 2

• CAA-related inflammation shares pathophysiology with amyloid-related imaging abnormalities (ARIA) seen in patients receiving amyloid-modifying therapies 1, 4

• Diagnostic approaches now include advanced neuroimaging techniques:

  • Gradient-echo T2* and susceptibility-weighted imaging for detecting microhemorrhages
  • Amyloid PET imaging (though it cannot distinguish vascular from parenchymal amyloid) 4

• Genetic risk factors play important roles in both sporadic and hereditary forms:

  • ApoE ε4 increases vascular Aβ deposition
  • ApoE ε2 is associated with CAA-related hemorrhage 7

Understanding the specific type of CAA is crucial for proper management, risk assessment, and potential therapeutic approaches, particularly as amyloid-modifying therapies continue to be developed for Alzheimer's disease.