Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies

Abstract

IMPORTANCEAfter more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance.OBJECTIVE To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti-β-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.EVIDENCE REVIEW In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine.FINDINGS Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs.CONCLUSIONS AND RELEVANCE Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies

“…The exact mechanisms of ARIA-E remain to be fully elucidated. The review of lessons learned from the last decade of research confirmed the ARIA Paradox as the most accredited pathophysiologic model to explain the biological complexity of ARIA-E. 1,4,5,10,12,42 According to this model, ARIA-E is a complex and multifactorial phenomenon resulting from the imbalance between the removal of Aβ deposited in plaques, which is attributed to the dose, time, and type of anti-Aβ (auto) antibodies, and the downstream effects that an excessive mobilization of Aβ can cause on intramural periarterial drainage pathways, 43 which may account for increased transient CAA, cerebrovascular impairment, greater vascular permeability, and an easier extravasation of proteinaceous fluid and VE, particularly in ApoE e4 carriers. 1,2,10,12,[44][45][46] In this proof-of-principle study, we extend the understanding of ARIA-E biology by providing in vivo evidence for an association between ARIA-E and microglial activation through multimodal and multiparametric MRI, CSF testing for anti-Aβ autoantibodies and AT(N) biomarkers, and 11 C-PK11195 PET longitudinal assessments in patients with CAA-ri, a spontaneous human model of the iatrogenic ARIA-E of AD immunotherapy.…”

“…The exact mechanisms of ARIA-E remain to be fully elucidated. The review of lessons learned from the last decade of research confirmed the ARIA Paradox as the most accredited pathophysiologic model to explain the biological complexity of ARIA-E. 1 , 4 , 5 , 10 , 12 , 42 According to this model, ARIA-E is a complex and multifactorial phenomenon resulting from the imbalance between the removal of Aβ deposited in plaques, which is attributed to the dose, time, and type of anti-Aβ (auto)antibodies, and the downstream effects that an excessive mobilization of Aβ can cause on intramural periarterial drainage pathways, 43 which may account for increased transient CAA, cerebrovascular impairment, greater vascular permeability, and an easier extravasation of proteinaceous fluid and VE, particularly in ApoE ε4 carriers. 1 , 2 , 10 , 12 , 44 – 46 …”

“…Considering that at least some degree of CAA is present in most patients with AD as well as older people, the burden of ARIA-E complications in the real clinical practice would be anticipated to potentially increase compared with the reported 43% incidence in the EMERGE and ENGAGE clinical trials with aducanumab. 1 , 10 , 12 , 20 , 28 , 42 Then, elucidating the nature and the response to treatment course of the neuroinflammation associated with ARIA-E will be of paramount importance for both diagnostic and treatment decisions. 1 …”

“…Considering that at least some degree of CAA is present in most patients with AD as well as older people, the burden of ARIA-E complications in the real clinical practice would be anticipated to potentially increase compared with the reported 43% incidence in the EMERGE and ENGAGE clinical trials with aducanumab. 1,10,12,20,28,42 Then, elucidating the nature and the response to treatment course of the neuroinflammation associated with ARIA-E will be of paramount importance for both diagnostic and treatment decisions. 1 In this framework, our findings give a strong support in the use of corticosteroids to manage the neuroinflammatory response mediated by increased CSF anti-Aβ (auto) antibodies 1,3 and highlight the urgency to define specific treatment and monitoring recommendations for ARIA-E. 1,10,12 Indeed, CSF anti-Aβ autoantibodies were elevated at disease presentation and decreased at follow-up when cerebral microglial activation was reduced.…”

Vascular Dysfunction Is Central to Alzheimer’s Disease Pathogenesis in APOE e4 Carriers

“…The strong effect of CAA is significant, as anti-Aβ antibody treatments such as aducanumab are not recommended for individuals with CAA due to the high rates of amyloid-related imaging abnormalities (ARIA) [61]. ARIAs are the main adverse event associated with anti-Aβ antibodies and a meta-analysis of clinical trials showed that APOE4 carriers were at the highest risk [62]. Notwithstanding the APOE4-specific pathomechanisms described, persons receiving anti-Aβ antibodies should be genotyped and split into APOE4 carriers and non-carriers.…”