The amyloid β-protein (Aβ) E22Q mutation of the rare disorder hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) causes severe cerebral amyloid angiopathy (CAA) with hemorrhagic strokes of mid-life onset and dementia. The mutation does not affect total Aβ production but may alter the Aβ1–42:Aβ1–40 ratio, and affect the proteolytic degradation of Aβ and its transport across the blood–brain barrier. Aβ E22Q aggregates faster into more stable amyloid-like fibrils than wild-type Aβ. Non-fibrillar Aβ(x-42) deposits precede the appearance of fibrils and the deposition of Aβ(x-40) in the vascular basement membrane. CAA severity tends to increase with age but may vary greatly among patients of comparable ages. Lumenal narrowing of affected blood vessels, leukoencephalopathy, CAA-associated vasculopathies, and perivascular astrocytosis, microgliosis, and neuritic degeneration complicate the development of HCHWA-D CAA. Parenchymal Aβ deposition is also enhanced in the HCHWA-D brain with non-fibrillar membrane-bound Aβ(x-42) deposits evolving into relatively fibrillar diffuse plaques variously associated with reactive astrocytes, activated microglia, and degenerating neurites. Plaque density tends to decrease with age. Neurofibrillary degeneration is absent or limited. HCHWA-D dementia is associated with CAA severity independently of Braak stage, age, and plaque density. Particularly, microaneurysms may contribute to the development of (small) hemorrhages/infarcts and the latter to cognitive decline in affected subjects. However, the relative importance of cerebral hemorrhages/infarcts, white matter damage and/or other CAA- or Aβ-related factors for cognitive deterioration in HCHWA-D remains to be determined.