(1) Background: The 2023 approval of lecanemab for early-stage Alzheimer\'s disease (AD) highlighted the need for routine 1.5T or 3.0T MRI scans to monitor amyloid-related imaging abnormalities (ARIAs). Regional disparities in MRI scan frequency, MRI scanner availability, and scanner magnetic field strengths could affect readiness for anti-amyloid therapy and lead to inconsistencies in ARIA detection nationwide. (2) Methods: We assessed regional variance in MRI scan frequency and field strength across Japan using the National Database (NDB) Open Data website, which summarizes Japanese public health insurance claims from the fiscal years (FYs) 2015 to 2021. We employed a mixed-effects model with prefecture-level random intercepts and slopes over time, subsequently categorizing prefectures into clusters based on MRI usage. (3) Results: 1.5T MRI was the most common magnetic field strength, remaining stable from FY2015 to FY2021. 3.0T MRI usage slightly increased, although the COVID-19 pandemic in FY2020 led to a maximum reduction of 5%. Prefecture-level variance was higher for 3.0T MRIs, with more frequent usage in western Japan. (4) Conclusions: This study highlights prefecture-level variance in MRI usage across Japan. The insights gained could be instrumental in improving healthcare preparedness for anti-amyloid treatment and patient management.

Recent advancements in Alzheimer\'s disease treatment have focused on the elimination of amyloid-beta (Aβ) plaque, a hallmark of the disease. Monoclonal antibodies such as lecanemab and donanemab can alter disease progression by binding to different forms of Aβ aggregates. However, these treatments raise concerns about adverse effects, particularly amyloid-related imaging abnormalities (ARIA). Careful assessment of safety, especially regarding ARIA, is crucial. ARIA results from treatment-related disruption of vascular integrity and increased vascular permeability, leading to the leakage of proteinaceous fluid (ARIA-E) and heme products (ARIA-H). ARIA-E indicates treatment-induced edema or sulcal effusion, while ARIA-H indicates treatment-induced microhemorrhage or superficial siderosis. The minimum recommended magnetic resonance imaging sequences for ARIA assessment are T2-FLAIR, T2* gradient echo (GRE), and diffusion-weighted imaging (DWI). T2-FLAIR and T2* GRE are necessary to detect ARIA-E and ARIA-H, respectively. DWI plays a role in differentiating ARIA-E from acute to subacute infarcts. Physicians, including radiologists, must be familiar with the imaging features of ARIA, the appropriate imaging protocol for the ARIA workup, and the reporting of findings in clinical practice. This review aims to describe the clinical and imaging features of ARIA and suggest points for the timely detection and monitoring of ARIA in clinical practice.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rapid but reversible autoimmune encephalopathy where spontaneous autoantibody reaction against amyloid beta deposited in cerebral blood vessels produces characteristic neuroinflammatory changes such as vasogenic edema and microhemorrhages on MRI. The term amyloid-related imaging abnormalities (ARIA) is sometimes used to describe these changes but are more often reserved for similar MRI signal abnormalities seen after administration of anti-amyloid immunotherapy, using treatment exposure as an antecedent. It is unclear if there is any biological basis for this dichotomized distinction. We report a case of severe CAA-ri after exposure to SARS-CoV-2 vaccine and performed a literature review of CAA-ri related to vaccination. CAA-ri precipitated by immunogenic triggers other than anti-amyloid therapy would lend support to the hypothesis that ARIA seen on MRI may represent the same disease underpinned by a shared anti-Aβ autoantibody response irrespective of etiology. A thorough history should be taken before labelling CAA-ri as spontaneous.

APOE-ε4 allele[s] is a risk factor for Alzheimer\'s disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, APOE-ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the APOE-ε4 allele\'s risk for non-ARIA AEs during AD clinical trials. We used data from the Critical Path for Alzheimer\'s Disease (CPAD) from the placebo arm of randomized controlled trials (RCT) for AD treatment. We determined whether AEs were reported more frequently in APOE-ε4 carriers, quantifying with reporting odds ratio (ROR) using a mixed effect model. We also evaluated the association between ROR levels and the prior probability that an AE is symptomatic ARIA. We analyzed 6,313 patients with AD or mild cognitive impairment in 28 trials. Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: \"delusion\" (ROR = 4.133), \"confusional state\" (ROR = 1.419), \"muscle spasms\" (ROR = 9.849), \"irritability\" (ROR = 12.62), \"sleep disorder\" (ROR = 2.944), or \"convulsion\" (ROR = 13.00). However, none remained significant after adjusting for Mini-Mental State Examination scores. There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE-ε4 carriers. The influence of APOE-ε4 allele[s] on the clinicians\' assessment of the likelihood of ARIA during safety monitoring in anti-amyloid beta monoclonal antibody treatment might be unchanged, thus maintaining the current level of awareness of clinicians of AEs.

BACKGROUND: Preclinical Alzheimer\'s disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer\'s disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.
OBJECTIVE: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.
METHODS: Phase 3, 4.5-year, multicenter, placebo-controlled trial.
METHODS: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study.
METHODS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.
METHODS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).
RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001).
CONCLUSIONS: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer\'s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer\'s disease.

Anti-amyloid immunotherapies have recently emerged as treatments for Alzheimer\'s disease. While these therapies have demonstrated efficacy in clearing amyloid-β and slowing cognitive decline, they have also been associated with amyloid-related imaging abnormalities (ARIA) which include both edema (ARIA-E) and hemorrhage (ARIA-H). Given that ARIA have been associated with significant morbidity in cases of antithrombotic or thrombolytic therapy, an understanding of mechanisms of and risk factors for ARIA is of critical importance for stroke care. We discuss the latest data regarding mechanisms of ARIA, including the role of underlying cerebral amyloid angiopathy, and implications for ischemic stroke prevention and management.

BACKGROUND: Donanemab, a monoclonal antibody directed against an insoluble, modified, N-terminal truncated form of amyloid beta, demonstrated efficacy and safety in patients with early, symptomatic Alzheimer\'s disease (AD) in the phase 3 TRAILBLAZER-ALZ 2 trial. Here, we report clinical outcomes, biomarkers, and safety results for the Japanese subpopulation.
METHODS: TRAILBLAZER-ALZ 2 (N = 1736) was conducted in eight countries, including Japan (enrollment June 2020-November 2021; database lock April 2023). Participants (60-85 years) with early, symptomatic AD (mild cognitive impairment/mild dementia), Mini-Mental State Examination score 20-28, and confirmed amyloid and tau pathology were randomized 1:1 (stratified by tau status) to intravenous donanemab (700 mg for three doses, then 1400 mg/dose) or placebo every 4 weeks for 72 weeks. Primary outcome was change from baseline to week 76 in integrated Alzheimer\'s Disease Rating Scale (iADRS) score. Other outcomes included clinical measures of cognitive and functional impairment, biomarkers, and safety.
RESULTS: Of 88 Japanese participants (43 placebo, 45 donanemab), 7 in each group discontinued. Least-squares mean (LSM) change from baseline in iADRS score at week 76 was smaller with donanemab than with placebo in the combined (low-medium tau and high tau) and low-medium tau (N = 76) subpopulations (LSM change difference: 4.43 and 3.99, representing 38.8% and 40.2% slowing of disease progression, respectively). Slowing of AD progression with donanemab was also observed for other clinical outcomes. Marked decreases in amyloid plaque and plasma phosphorylated tau 217 were observed; amyloid clearance (< 24.1 Centiloids) was observed in 83.3% of the combined donanemab and 0% of the combined placebo groups. Amyloid-related imaging abnormalities of edema/effusions occurred in ten (22.2%) donanemab-treated participants (one [2.2%] symptomatic) and one (2.3%) placebo-treated participant.
CONCLUSIONS: The overall efficacy and safety of donanemab in Japanese participants were similar to the global TRAILBLAZER-ALZ 2 population.
BACKGROUND: ClinicalTrials.gov identifier: NCT04437511.

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by the accumulation of amyloid-beta peptide (Aβ) within the leptomeninges and smaller blood vessels of the brain. CAA can be both noninflammatory and inflammatory, and the inflammatory version includes Aβ-related angiitis (ABRA). ABRA is a vasculitis of the central nervous system related to an inflammatory response to Aβ in the vascular walls, which necessitates differentiating ABRA from noninflammatory CAA, as ABRA may require immunosuppressive treatment. MR imaging is typically the most effective imaging modality of choice to screen for these conditions, and they should be obtained at varying time points to track disease progression.

BACKGROUND: Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer\'s disease. UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer\'s disease.
METHODS: A 78-week, randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 2a study was conducted in Taiwan. Participants were randomised in a 1:1:1 ratio to receive seven intramuscular injections of UB-311 (Q3M arm), or five doses of U311 with two doses of placebo (Q6M arm), or seven doses of placebo (placebo arm). The primary endpoints were safety, tolerability, and immunogenicity of UB-311. Safety was assessed in all participants who received at least one dose of investigational product. This study was registered at ClinicalTrials.gov (NCT02551809).
RESULTS: Between 7 December 2015 and 28 August 2018, 43 participants were randomised. UB-311 was safe, well-tolerated, and generated a robust immune response. The three treatment-emergent adverse events (TEAEs) with the highest incidence were injection-site pain (14 TEAEs in seven [16%] participants), amyloid-related imaging abnormality with microhaemorrhages and haemosiderin deposits (12 TEAEs in six [14%] participants), and diarrhoea (five TEAEs in five [12%] participants). A 97% antibody response rate was observed and maintained at 93% by the end of the study across both UB-311 arms.
CONCLUSIONS: These results support the continued development of UB-311.
BACKGROUND: Vaxxinity, Inc. (Formerly United Neuroscience Ltd.).

Excess accumulation and aggregation of toxic soluble and insoluble amyloid-β species in the brain are a major hallmark of Alzheimer\'s disease. Randomized clinical trials show reduced brain amyloid-β deposits using monoclonal antibodies that target amyloid-β and have identified MRI signal abnormalities called amyloid-related imaging abnormalities (ARIA) as possible spontaneous or treatment-related adverse events. This review provides a comprehensive state-of-the-art conceptual review of radiological features, clinical detection and classification challenges, pathophysiology, underlying biological mechanism(s) and risk factors/predictors associated with ARIA. We summarize the existing literature and current lines of evidence with ARIA-oedema/effusion (ARIA-E) and ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid clinical trials and therapeutic development. Both forms of ARIA may occur, often early, during anti-amyloid-β monoclonal antibody treatment. Across randomized controlled trials, most ARIA cases were asymptomatic. Symptomatic ARIA-E cases often occurred at higher doses and resolved within 3-4 months or upon treatment cessation. Apolipoprotein E haplotype and treatment dosage are major risk factors for ARIA-E and ARIA-H. Presence of any microhaemorrhage on baseline MRI increases the risk of ARIA. ARIA shares many clinical, biological and pathophysiological features with Alzheimer\'s disease and cerebral amyloid angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with such underlying conditions to allow clinicians and researchers to further understand, deliberate and investigate on the combined effects of these multiple pathophysiological processes. Moreover, this review article aims to better assist clinicians in detection (either observed via symptoms or visually on MRI), management based on appropriate use recommendations, and general preparedness and awareness when ARIA are observed as well as researchers in the fundamental understanding of the various antibodies in development and their associated risks of ARIA. To facilitate ARIA detection in clinical trials and clinical practice, we recommend the implementation of standardized MRI protocols and rigorous reporting standards. With the availability of approved amyloid-β therapies in the clinic, standardized and rigorous clinical and radiological monitoring and management protocols are required to effectively detect, monitor, and manage ARIA in real-world clinical settings.