Anti-abeta antibodies in CSF: markers for therapies?

Advances in the biomarkers discovery for Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA) has sensibly accelerated the design of novel disease-modifying therapies (DMT), with different promising anti amyloid-beta (Aβ) therapeutic antibodies already in Phase II and III. Active and passive immunotherapies, however, have been both characterized by the occurrence of Amyloid-Related Imaging Abnormalities (ARIA), probably related to the drug and APOEε4 allele dose. In the last decade, ARIA have severely limited the development of immunotherapy, leading to the exclusion of several patients from the opportunity to be treated. The discovery of safety biomarkers to avoid, or at least enable, the early detection of ARIA will represent an important challenge to help stratify and personalize treatments, increasing the chances for developing more effective DMT. Biomarkers will have critical implications to predict individuals in a particular disease stage chosen as the therapeutic window for a specifi c treatment, especially as we move to more large and long duration prevention trials based on the selective enrolment of positive Amyloid-PET and/or CSF cases, potentially increasing the risk to incur in ARIA side effects of treatment. It is quite clear that without effective biomarkers we will have the consequence of further unacceptable delays in fi nding a cure for this devastating disease. Through the iCAβ International Network, we pioneered in showing that elevated CSF anti-Aβ autoantibodies are linked to a transient vascular leakage at the sites of major Aβ removal, causing a shift in CAA accumulation and increased vascular permeability, eventually leading to ARIA