Views and Perceptions of Amyloid Imaging in a Preclinical Alzheimer's Disease Trial.

Background: Many cognitively unimpaired older adults are interested in learning their Alzheimer's disease (AD) biomarker status, but little is known about motivations to undergo biomarker testing and result disclosure in the setting of preclinical AD trials.

Objectives: Examine whether motivations to undergo AD biomarker testing and disclosure differ for individuals who have elevated amyloid compared to those with not elevated amyloid, and whether disclosure of amyloid results impacts participants' motivations.

Design, Setting, Participants: We conducted post-hoc analyses using data from the EARLY study, a preclinical AD trial of the beta-secretase inhibitor atabecestat.

Immediate Reactions to Alzheimer Biomarker Disclosure in Cognitively Unimpaired Individuals in a Global Truncated Randomized Trial.

Background And Objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals.

Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician.

The Discovery of Anti-Yo (Anti-PCA1) Antibody in Patients with Paraneoplastic Cerebellar Degeneration: Opening a Window into Autoimmune Neurological Disease.

Prior to 1982, ovarian and certain other cancers were known to have a rare complication of progressive cerebellar ataxia, a disorder characterized pathologically by severe-often total-obliteration of cerebellar Purkinje cells. However, the cause of cerebellar injury in these patients was unknown. In that year, we began studies in which sera from individuals with this disorder were reacted with frozen sections of human cerebellum.

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

Background: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials.

Objective: To evaluate the association between amyloid (Aβ) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS).

Design: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs).

Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior.

The pathway to secondary prevention of Alzheimer's disease.

Alzheimer's disease (AD) is a continuum consisting of a preclinical stage that occurs decades before symptoms appear. As researchers make advances in investigating the continuum, the importance of developing drugs for secondary prevention is garnering increased discussion. For efficacious drug development for secondary prevention it is important to define what are the earliest biological stages of AD.

Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

Background: Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed.

Methods: In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once daily (later reduced to 5 and 25 mg) for 6 months.

Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

Background: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD).

Objectives: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup.

Design: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom.

Listening to the HysterSisters: A Retrospective Keyword Frequency Analysis of Conversations About Hysterectomy Recovery.

Background: In the postoperative period, individual patient experiences vary widely and are based on a diverse set of input variables influenced by all stakeholders in and throughout the surgical process. Although clinical research has primarily focused on clinical and administrative datasets to characterize the postoperative recovery experience, there is increasing interest in patient-reported outcome measures (PROMs). The growth of online communities in which patients themselves participate provides a venue to study PROMs directly.

Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies.

Background: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer's disease in bapineuzumab phase III studies.

Objectives: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function.

Methods: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists.

Psychometric Evaluation of the Neuropsychological Test Battery in Individuals with Normal Cognition, Mild Cognitive Impairment, or Mild to Moderate Alzheimer's Disease: Results from a Longitudinal Study.

Background: The Neuropsychological Test Battery (NTB) is a combination of widely used clinical neuropsychological tests measuring memory and executive function and was designed to overcome some of the limitations of the traditionally used Alzheimer's disease Assessment Scale - Cognitive subscale (ADAS-Cog). A previously reported account indicated high levels of NTB reliability in patients with mild-to-moderate Alzheimer's disease (AD) and mild cognitive impairment (MCI).

Objectives: We examined capacity of the Neuropsychological Test Battery (NTB) and its component subtests to measure cognitive change over time.

Long-Term Safety and Efficacy of Bapineuzumab in Patients with Mild-to-Moderate Alzheimer's Disease: A Phase 2, Open-Label Extension Study.

Background: Bapineuzumab is a humanized anti-amyloid-beta (Aβ) monoclonal antibody directed at lowering the cerebral Aβ deposit in Alzheimer's disease (AD).

Objective: This phase 2, open-label extension (OLE) study evaluated long-term safety and efficacy of bapineuzumab in patients with the mild-to-moderate AD.

Methods: Patients (58-78 years) who completed either of two randomized, placebo-controlled, doubleblind studies (subcutaneous [SC] single-dose-escalation, or intravenous (IV) multiple-ascending-dose)) entered the OLE.

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Bapineuzumab: A Single-Ascending-Dose Study in Patients With Mild to Moderate Alzheimer Disease.

This study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending subcutaneous doses of bapineuzumab in patients with mild to moderate Alzheimer disease. Forty patients were randomized across 5 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 80 mg; 8 patients each [bapineuzumab 6; placebo 2]). The incidence of treatment-emergent adverse events (TEAEs) was higher in pooled bapineuzumab cohorts (83%) than in the pooled placebo group (27.

Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients.

Background: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]).

Objectives: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers).

Methods: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists.

Validation of an MRI Rating Scale for Amyloid-Related Imaging Abnormalities.

Introduction: Immunotherapeutic agents against amyloid beta (Aβ) are associated with adverse events, including amyloid-related imaging abnormalities with edema and effusion (ARIA-E). Recently, a magnetic resonance imaging (MRI) rating scale was developed for ARIA-E detection and classification. The aim of this study was to validate the use of this rating scale in a larger patient group with multiple raters.

Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study.

Background: A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer's disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome.

Methods: Randomized patients (N = 2045) were divided into subgroups based on memantine use.

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer's disease.

Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD).

Objectives: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated.

Long-term safety and tolerability of bapineuzumab in patients with Alzheimer's disease in two phase 3 extension studies.

Background: Immunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer's disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols.

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

Background: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD).

Methods: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.

Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab.

Background: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients.

Objective: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling.

Methods: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future.