Research

Inflammatory Cerebral Amyloid Angiopathy and Alzheimer’s disease Biomarkers (iCAβ)

Recent advances in the biomarkers to diagnose AD and CAA have accelerated the design of more effective Aβ disease-modifying therapies (DMT). Immunotherapy against amyloid-β has shown potential as DMTs but its use in clinical trials has been severely limited by the occurrence of ARIA and adverse clinical events. ARIA represents a critical and unresolved issue that has leaded to several discontinuations and adjustment of the therapeutic plans over the past years, with a negative impact on the treatment opportunity of patients.

More research is need into fluid- or imaging-biomarkers (or most likely a combination of both) to diagnose and to predict these events. Of relevance, the more recent trials based on the selective enrolment of AD patients with positive Amyloid-PET uptake (and/or CSF) will potentially increase the risk. Notably, the first phase I immunotherapeutic (ponezumab) trial for sporadic CAA has recently been launched.

The discovery and validation of useful diagnostic biomarkers will have critical implications if such biomarkers could avoid the occurrence of the serious side-effects of clinical trials.

The recent evidences on the potential increased mobilization of deposited Aβ into and out of blood vessels by Aβ antibodies, and their temporally-associated aggravating CAA-related vascular effects, have raise new hopes in understanding, predicting, and monitoring this potential hazard. The hypothesis linking anti-Aβ immunization strategies to ARIA seems to be an augmented immune response directed toward deposited Aβ, where anti-Aβ antibody administration and the transient manifestation of ARIA could be related to a rapid removal of the deposited cerebrovascular Aβ, strictly modulated by antibody dosage prior to a nearly complete Aβ-clearance.

Interestingly, this is in agreement with the recent demonstration of elevated anti-Aβ autoantibodies in the cerebrospinal fluid of patients affected by Cerebral Amyloid Angiopathy-related inflammation (CAA-ri), a distinctly rare, but aggressive, meningoencephalitis affecting about 5% of CAA patients, as pioneeringly shown by Dr Piazza through the iCAβ International Network.

CAA-ri may thus represent a spontaneous “human model” of the ARIA occurring in AD-treated patients, mediated by a specific autoimmune reaction against the deposited perivascular Aβ in an aged and compromised cerebrovascular background. These events are accompanied by massive drainage of Aβ from the brain and vascular deposits to its soluble pools, along with higher amounts of anti-Aβ autoantibodies. Accordingly, in line with data from passive immunization, we observed a reduction of both autoantibodies and neurodegenerative markers (tau, P-tau, Aβ40 and Aβ42) after clinical and radiological remission of ARIA, either spontaneously or after immunosuppressive treatment. Anti-Aβ antibodies may thus play a key role in the process, causing a shift in cerebral amyloid accumulation and increased vascular permeability eventually leading to ARIA.

These aspects are timely and could provide an important challenge for the field.

If confirmed in a large number of patients, particularly in biopsy-proven cases such as we are collecting through the iCAβ International Network, the possibility to follow up the dosage of CSF anti-Aβ antibody would allow maintaining a putative “therapeutic window” for the safe clearance of vascular Aβ, limiting the occurrence of CAA-related consequences, placing anti-Aβ antibodies as a promising biomarker not only for CAA-ri diagnostic confirmation but also for the current ongoing clinical trials in AD and CAA.

GENERAL OBJECTIVE

To establish the largest biobank of patients today existing for the study of CAAri. We can already rely upon the largest and well-characterized cohort of CAA-ri collected World-Wide (31 Centres from 12 Countries).

SPECIFIC OBJECTIVES

1) Validation of the first ultra sensitive ELISA-based test for early CAA-ri's diagnosis and treatment follow-up.

2) Investigation of the mechanisms by which the anti-Aβ autoantibodies facilitate Aβ removal and participate in the development of the CAA-related acute events (ARIA-like events)

3) Identification of new biomarkers and risk factors for ARIA, to be used for patient stratification, therapeutic tailoring and treatment follow up in AD and CAA clinical trials.