Pathogenetic role of anti-AB autoantibodies in Cerebral Amyloid Angiopathy-related inflammation and Alzheimer's disease

Cerebral amyloid angiopathy (CAA) is pathologically characterized by the progressive deposition of amyloid-β (Aβ) protein in the walls of small/medium sized arteries and capillaries in the cerebral cortex and overlying leptomeninges, representing an important cause of spontaneous intracerebral haemorrhage and cognitive impairment. Interestingly, a subgroup of CAA patients has been shown to develop vascular inflammation of the affected vessels, associated with vasogenic edema (VE) and to a rapid cognitive decline. This condition, known as CAA-related inflammation (CAA-ri), presents with acute or subacute neurological impairment, behavioral changes, seizures and focal neurological deficits. A definite diagnosis of CAA-ri requires brain and leptomeningeal biopsy that shows perivascular inflammation associated with Aβ laden vessels and signs of vasculitis. This distinct syndrome has parallels with what observed in about 5-10% of patients affected by Alzheimer’s disease (AD) who developed reversible VE after passive immunization with the anti-Aβ antibody bapineuzumab, where postmortem examination revealed inflammation and/or vasculitis associated with CAA, implying the discontinuation of the therapeutic protocol. Moreover, recent imaging data on the location of ARIA-E have shown that up to 17% of the treated patients showed signs of VE, even if in the absence of clinical correlates and directly related to the drug dose. Herein, thanks to a novel technique for the ultra sensitive evaluation of anti-Aβ (patent application pending), for the first time, we confirmed a direct involvement of these antibodies during the course Pag. of disease in the CSF of 10 CAA-ri, compared to 8 CAA and 20 healthy subjects, demonstrating that the concentration of anti-Aβ is specifically increased during the acute phase of the disease. Moreover, we reported a progressive reduction of autoantibodies concentration following steroid treatment, according to clinical-radiological improvement. As a further proof, a spontaneous decrease of anti-Aβ in patients without any immunosuppressant treatment was observed, finally proving that this event is not secondary to an unspecific effect of treatment, but strictly related to the disease progression. Our data support the hypothesis that the pathogenesis of CAA-ri is caused by a specific autoimmune reaction directed against Aβ, directly mediated by anti-Aβ autoantibodies. The outcomes implied by antibodies dosage in the CSF may be proposed to support future accessible targets for early diagnosis and follow-up, and as a novel surrogate biomarkers for clinical trials of disease modifying therapies.