Progression of cerebral amyloid angiopathy: a pathophysiological framework.

Cerebral amyloid angiopathy, which is defined by cerebrovascular deposition of amyloid β, is a common age-related small vessel pathology associated with intracerebral haemorrhage and cognitive impairment. Based on complementary lines of evidence from in vivo studies of individuals with hereditary, sporadic, and iatrogenic forms of cerebral amyloid angiopathy, histopathological analyses of affected brains, and experimental studies in transgenic mouse models, we present a framework and timeline for the progression of cerebral amyloid angiopathy from subclinical pathology to the clinical manifestation of the disease. Key stages that appear to evolve sequentially over two to three decades are (stage one) initial vascular amyloid deposition, (stage two) alteration of cerebrovascular physiology, (stage three) non-haemorrhagic brain injury, and (stage four) appearance of haemorrhagic brain lesions. This timeline of stages and the mechanistic processes that link them have substantial implications for identifying disease-modifying interventions for cerebral amyloid angiopathy and potentially for other cerebral small vessel diseases.

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Declaration of interests EAK reports funding from the Dutch CAA Foundation, Dutch Alzheimer Foundation, Dutch Heart Foundation, and KNAW van Leersum. SJvV reports funding from Therini Bio. MJPvO reports funding to his institution from Alnylam and Biogen, research funding from Phillips, and an unpaid leadership role for ISMRM study group on Neurofluids. MAAvW reports funding to her institution from Alnylam and Biogen. HRS reports funding to his institution from Alnylam and Biogen and lecture honoraria for ACNEM practitioners. ZS reports funding from the Alzheimer's society of Canada. MAvB reports funding to his institution from Alnylam and Biogen and research funding from Phillips. GMT reports funding to her institution from Alynlam and Biogen. EES reports consulting fees from Eli Lilly. DJW reports consulting fees from Alnylam and NovoNordisk; honoraria from NovoNordisk, Bayer, and Alexion; and unpaid leadership roles with the National Institute for Health and Care Excellence and the British & Irish Association of Stroke Physicians. MJHW reports funding to her institution from Alynlam and Biogen. SMG reports support from the Frechette Foundation and an unpaid leadership role for the International CAA Association.