Joshua D. Grill

IMPORTANCE: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. OBJECTIVES: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. INTERVENTIONS: Oral avagacestat or placebo daily. MAIN OUTCOMES AND MEASURE: Safety and tolerability of avagacestat. RESULTS: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures. CONCLUSIONS AND RELEVANCE: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00890890.

Among the key challenges in Alzheimer's disease drug development is the timely completion of clinical trials. Unfortunately, clinical trials often suffer from slow or insufficient enrollment. Successful clinical trial recruitment describes a balance between expeditiously achieving full enrollment and ensuring an appropriate study sample. Investigators face a number of challenges to the successful negotiation of this balance. The failure to address these challenges means that drug development may take more time and money and that trial results may not adequately represent drug efficacy or may not be applicable beyond the study. We review the challenges to recruitment and retention in Alzheimer's disease clinical trials and present a framework to address them.

OBJECTIVES: To characterize caregiver strain, depressive symptoms, and self-efficacy for managing dementia-related problems and the relationship between these and referring provider type. DESIGN: Cross-sectional observational cohort. SETTING: Urban academic medical center. PARTICIPANTS: Caregivers of community-dwelling adults with dementia referred to a dementia care management program. MEASUREMENTS: Caregivers were surveyed and completed the Patient Health Questionnaire (PHQ-9) about themselves; the Modified Caregiver Strain Index; the Neuropsychiatric Inventory Questionnaire, which measures patient symptom severity and related caregiver distress; and a nine-item caregiver self-efficacy scale developed for the study. RESULTS: Of 307 patient-caregiver dyads surveyed over a 1-year period, 32% of caregivers reported confidence in managing dementia-related problems, 19% knew how to access community services to help provide care, and 28% agreed that the individual's provider helped them work through dementia care problems. Thirty-eight percent reported high levels of caregiver strain, and 15% reported moderate to severe depressive symptoms. Caregivers of individuals referred by geriatricians more often reported having a healthcare professional to help work through dementia care problems than those referred by internists, family physicians, or other specialists, but self-efficacy did not differ. Low caregiver self-efficacy was associated with higher caregiver strain, more caregiver depressive symptoms, and caring for an individual with more-severe behavioral symptoms. CONCLUSION: Most caregivers perceived inadequate support from the individual's provider in managing dementia-related problems, reported strain, and had low confidence in managing caregiving. New models of care are needed to address the complex care needs of individuals with dementia and their caregivers.

Pain has long been thought to wax and wane in relative proportion to fluctuations in the intensity of noxious stimuli. Dynamic aspects of nociceptive processing, however, remain poorly characterized. Here we show that small decreases (+/-1-3 degrees C) in noxious stimulus temperatures (47-50 degrees C) evoked changes in perceived pain intensity that were as much as 271% greater than those of equal magnitude increases. These decreases in perceived pain intensity were sufficiently large to be indistinguishable from those evoked by 15 degrees C decreases to clearly innocuous levels. Furthermore, decreases in pain ratings following noxious stimulus offset were significantly greater than those occurring during adaptation to constant temperature stimuli. Together, these findings indicate that an analgesic mechanism is activated during noxious stimulus offset. This analgesic phenomenon may serve as a temporal contrast enhancement mechanism to amplify awareness of stimulus offset and to reinforce escape behaviors. Disruption of this mechanism may contribute importantly to chronic pain.

Importance: Underrepresentation of many racial/ethnic groups in Alzheimer disease (AD) clinical trials limits generalizability of results and hinders opportunities to examine potential effect modification of candidate treatments. Objective: To examine racial and ethnic differences in recruitment methods and trial eligibility in a multisite preclinical AD trial. Design, Setting, and Participants: This cross-sectional study analyzed screening data from the Anti-Amyloid in Asymptomatic AD study, collected from April 2014 to December 2017. Participants were categorized into 5 mutually exclusive ethnic/racial groups (ie, Hispanic, Black, White, Asian, and other) using participant self-report. Data were analyzed from May through December 2020 and included 5945 cognitively unimpaired older adults between the ages of 65 and 85 years screened at North American study sites. Main Outcomes and Measures: Primary outcomes included recruitment sources, study eligibility, and ineligibility reasons. To assess the probability of trial eligibility, regression analyses were performed for the likelihood of being eligible after the first screening visit involving clinical and cognitive assessments. Results: Screening data were included for 5945 participants at North American sites (mean [SD] age, 71.7 [4.9] years; 3524 women [59.3%]; 5107 White [85.9%], 323 Black [5.4%], 261 Hispanic [4.4%], 112 Asian [1.9%], and 142 [2.4%] who reported race or ethnicity as other). Recruitment sources differed by race and ethnicity. While White participants were recruited through a variety of sources, site local recruitment efforts resulted in the majority of Black (218 [69.2%]), Hispanic (154 [59.7%]), and Asian (61 [55.5%]) participants. Participants from underrepresented groups had lower mean years of education (eg, mean [SD] years: Hispanic participants, 15.5 [3.2] years vs White participants, 16.7 [2.8] years) and more frequently were women (226 [70.0%] Black participants vs 1364 [58.5%] White participants), were unmarried (184 [56.9%] Black participants vs 1364 [26.7%] White participants), and had nonspousal study partners (237 [73.4%] Black participants vs 2147 [42.0%] White participants). They were more frequently excluded for failure to meet cognitive inclusion criteria (eg, screen failures by specific inclusion criteria: 147 [45.5%] Black participants vs 1338 [26.2%] White participants). Compared with White participants, Black (odds ratio [OR], 0.43; 95% CI, 0.34-0.54; P < .001), Hispanic (OR, 0.53; 95% CI, 0.41-0.69; P < .001), and Asian participants (OR, 0.56; 95% CI, 0.38-0.82; P = .003) were less likely to be eligible after screening visit 1. Conclusions and Relevance: Racial/ethnic groups differed in sources of recruitment, reasons for screen failure, and overall probability of eligibility in a preclinical AD trial. These results highlight the need for improved recruitment strategies and careful consideration of eligibility criteria when planning preclinical AD clinical trials.