The E22Q mutation of amyloid beta protein (Abeta) in the rare disease hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic stroke in middle age and dementia. The mutation does not affect overall Abeta production, but may alter the ratio of Abeta1-42 to Abeta1-40 and impair proteolytic degradation of Abeta and its transport across the blood-brain barrier. Abeta E22Q aggregates more rapidly into more stable amyloid-like fibrils than wild-type Abeta. Nonfibrillar Abeta(x-42) deposition precedes the appearance of fibrils and the deposition of Abeta(x-40) in the vascular basement membrane. The severity of CAA tends to increase with age but can vary widely in patients of comparable age. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA-associated vasculopathies, and perivascular astrocytosis,
Parenchymal Abeta deposits are also increased in the HCHWA-D brain, with nonfibrillar, membrane-bound Abeta(x-42) deposits evolving into relatively fibrillar, diffuse plaques associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends to decrease with age.
Neurofibrillary degeneration is absent or minimal.
HCHWA-D dementia is associated with CAA severity independent of age and plaque density. In particular, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and these to cognitive decline in affected individuals.
However, the relative importance of cerebral hemorrhage/infarcts, white matter damage, and/or other CAA- or Abeta-related factors for cognitive decline in HCHWA-D remains to be determined.