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Clinical trials for Alzheimers disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimers clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panels recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.

BackgroundThere is a need for feasible, scalable assessments to detect cognitive impairment and decline. The Cogstate Brief Battery (CBB) is validated for Alzheimer's disease (AD) and in unsupervised and bring your own device contexts. The CBB has shown usability for self-completion in the home but has not been employed in this way in a multisite clinical trial in AD.ObjectiveThe objective of the pilot was to evaluate feasibility of at-home, self-completion of the CBB in the Alzheimer's Disease Neuroimaging Initiative (ADNI) over 24 months.MethodsThe CBB was included as a pilot for cognitively normal (CN) and mild cognitive impairment (MCI) participants in ADNI-2, invited to take the assessment in-clinic, then at at-home over a period of 24 months follow-up. Data were analyzed to explore acceptability/usability, concordance of in-clinic and at-home assessment, and validity.ResultsData were collected for 104 participants (46 CN, 51 MCI, and 7 AD) who consented to provide CBB data. Subsequent analyses were performed for the CN and MCI groups only. Test completion rates were 100%for both the first in-clinic supervised and first at-home unsupervised assessments, with few repeat performances required. However, available follow-up data declined sharply over time. Good concordance was seen between in-clinic and at-home assessments, with non-significant and small effect size differences (Cohen's d between -0.04 and 0.28) and generally moderate correlations (r = 0.42 to 0.73). Known groups validity was also supported (11/16 comparisons with Cohen's d≥0.3).ConclusionThese data demonstrate the feasibility of use for the CBB for unsupervised at-home, testing, including MCI groups. Optimal approaches to the application of assessments to support compliance over time remain to be determined.

Objective/introductionUnemployment can negatively impact quality of life among patients with schizophrenia. Employment status depends on ability, opportunity, education, and cultural influences. A clinician-rated scale of work readiness, independent of current work status, can be a valuable assessment tool. A series of studies were conducted to create and validate a Work Readiness Questionnaire (WoRQ) for clinicians to assess patient ability to engage in socially useful activity, independent of work availability.MethodsContent validity, test-retest and inter-rater reliability, and construct validity were evaluated in three separate studies.ResultsContent validity was supported. Cronbach's α was 0.91, in the excellent range. Clinicians endorsed WoRQ concepts, including treatment adherence, physical appearance, social competence, and symptom control. The final readiness decision showed good test-retest reliability and moderate inter-rater reliability. Work readiness was associated with higher function and lower levels of negative symptoms. Low positive and high negative predictive values confirmed the concept validity.DiscussionThe WoRQ has suitable psychometric properties for use in a clinical trial for patients with a broad range of symptom severity. The scale may be applicable to assess therapeutic interventions. It is not intended to assess eligibility for supported work interventions.ConclusionsThe WoRQ is suitable for use in schizophrenia clinical trials to assess patient work functional potential.

Abstract Background There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS. Methods Forty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability. Results The composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohen's d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired. Conclusions Preliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition.

An evolving paradigm shift in the diagnostic conceptualization of Alzheimer's disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer's Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer's disease treatment earlier in the disease continuum. As a result, the field as a whole is now concentrated on exploring the next-generation of cognitive and functional outcome measures that will support clinical trials focused on treating the slow slide into cognitive and functional impairment. With this backdrop, the International Society for CNS Clinical Trials and Methodology convened semi-annual working group meetings which began in spring of 2012 to address methodological issues in this area. This report presents the most critical issues around primary outcome assessments in Alzheimer's disease clinical trials, and summarizes the presentations, discussions, and recommendations of those meetings, within the context of the evolving landscape of Alzheimer's disease clinical trials. [ABSTRACT FROM AUTHOR]

Introduction Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer’s disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein (APOE) β4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer’s patients to investigate relationships between task performance and both APOE status and cerebrospinal fluid (CSF) Aβ42 levels. Methods The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild-moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured. Results APOE β4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity. Conclusions These are to our knowledge the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD; as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in APOE β4 homocygotes. [ABSTRACT FROM AUTHOR]

Introduction: Recent initiatives have resulted in guidelines for the assessment of cognitive function in specific clinical populations including the MATRICS consensus cognitive test battery for schizophrenia and the EMEA guideline on medicinal products for the treatment of Alzheimer s disease and other dementias. There are a number of common criteria that emerge, including assessment of cognition at the level of individual cognitive domains; validation; utility; utility as a repeated measure; and data allowing interpretation of results and understanding of the clinical relevance (i.e., normative/relationship to functional outcomes). It is apparent that such common criteria could usefully be applied to cognitive function assessment in all clinical populations. The publication of normative data is of use in the interpretation of clinical trials data. Methods: Five-hundred and seventy (570) patients with newly diagnosed epilepsy, aged 12–75 years, from 21 countries within Europe, Latin America, and Australasia, not previously exposed to AEDs, were recruited to a clinical trial comparing the efficacy and safety of remacemide versus carbamazepine. Patients completed a 30 minute cognitive test battery comprised of the CDR System; Rey auditory verbal learning test; color-word Stroop test; symbol digit modalities test; Lafayette grooved pegboard; digit cancellation test; and the non-verbal matrices subtest of the Kaufman brief intelligence test. Normative data in treatment-naïve patients across the studied age range were generated. Results: Assessments showed a common relationship with age, with those patients in the younger adult age cohorts tending to perform better on all measures than older patients and also than the youngest age cohort patients. Conclusions: These data may be useful in the analysis and interpretation of cognitive assessment data from clinical trials of AEDs and/or studies in similar patient populations. Financial disclosure: This study was sponsored by AstraZeneca. None of the authors has a financial relationship with the sponsor. [Copyright &y& Elsevier]

Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a "clinically meaningful outcome" in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19-20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future., Competing Interests: AW is a full‐time employee and shareholder of Eli Lilly and Company. AA declares stock ownership and consulting fees from Alzeca Inc, stock ownership in Sensulin LLC. CJE is a full‐time employee of Cogstate Ltd. MG is a full‐time employee of Abbvie, Inc. DSM is a full‐time employee of Signant Health. CR is a full‐time employee of MedAvante‐ProPhase. JMR, previously with Rodin Therapeutics, at time of publication is a full‐time employee of Carnot Pharma, LLC dba RA Ventures. GW is a full‐time employee of Boehringer Ingelheim. DSK served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences but receives no personal compensation. He receives research support from the NIH. AMS receives support from the NIH/NIA, the Larry L. Hillblom Foundation, and the Bluefield Project to Cure FTD. MCC, CW are full‐time employees of the Alzheimer's Association., (© 2021 the Alzheimer's Association.)