Investigating the Factor Structure of the Preclinical Alzheimer Cognitive Composite and Cognitive Function Index across Racial/Ethnic, Sex, and Aß Status Groups in the A4 Study.

BACKGROUND: Disparities in Alzheimer's disease (AD) are well-documented among different racial/ethnic groups and between sex/genders. Neuropsychological assessment provides important information about cognitive changes and can offer valuable insights into disparities. However, neuropsychological measures must be comparable across racial/ethnic and sex/gender groups to accurately interpret disparities. OBJECTIVES: To evaluate measurement invariance (equivalence) of the Preclinical Alzheimer Cognitive Composite (PACC) and the Cognitive Function Index across racial/ethnic, sex/gender, and ß-amyloid (Aß) status groups. DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of screening data from the Anti-Amyloid in Asymptomatic AD (A4) Study. The study enrolled participants aged 65-85 from sites across the United States, Canada, Australia, and Japan. MEASUREMENTS: Participants completed the PACC and the Cognitive Function Index. Participants classified as cognitively normal also underwent a Positron Emission Tomography (PET) scan to determine Aß status. RESULTS: Participants self-identified as non-Hispanic White (n=5241), non-Hispanic Black (n=267), Asian (n=228), or Hispanic White (n=225) as well as male (n=2885) or female (n=3076). Among those who underwent a PET scan, 3115 were classified as Aß- and 1309 were classified as Aß+. We found support for a one-factor model for both the PACC and Cognitive Function Index across the full sample and in samples stratified by race/ethnicity, sex/gender, and Aß status. The one-factor model of the PACC and Cognitive Function Index demonstrated scalar measurement invariance across racial/ethnic, sex/gender, and Aß status groups. CONCLUSIONS: Our findings suggest that performance on the PACC and Cognitive Function Index can be compared across the racial/ethnic, sex/gender, and Aß status groups examined in this study.

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

Everyday Functioning and Entorhinal and Inferior Temporal Tau Burden in Cognitively Normal Older Adults.

BACKGROUND: Performance of cognitively complex "instrumental activities of daily living" (IADL) has previously been related to amyloid deposition in preclinical Alzheimer's disease. OBJECTIVES: We aimed to investigate the relationship between IADL performance and cerebral tau accumulation in cognitively normal older adults. DESIGN: Cross-sectional. SETTING: Data was collected in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. PARTICIPANTS: Participants (n = 447, age 71.9±4.9 years, 57.5% female) who underwent tau positron emission tomography were selected from the A4 and LEARN studies. MEASUREMENTS: IADL performance was measured using the self- and study partner-reported versions of the Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument (ADCS ADL-PI). We also investigated discordance between participants and their study partners. Cross-sectional associations between entorhinal and inferior temporal tau (independent variables) and ADCS ADL-PI total scores, item-level scores and discordance (dependent variables) were investigated in linear and logistic regressions. Analyses were adjusted for age, sex and education and a tau by amyloid interaction was also included. RESULTS: Participants and their study partners reported high levels of IADL performance. Entorhinal and inferior temporal tau were related to study partner but not to self-reported total ADCS ADL-PI scores. The association was not retained after adjustment for global cerebral amyloid burden. At the item level, greater entorhinal tau was associated with study partner-reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008) and difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Greater inferior temporal tau was associated with self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018) and study partner-reported difficulties remembering the details of TV programs and movies (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Discordance between participant and study partner-report was more likely with greater entorhinal (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) and inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002). DISCUSSION: We found a cross-sectional relationship between study partner-reported everyday functioning and tau in cognitively normal older adults. Participants were more likely to self-report difficulties differently from their study partners when tau burden was higher. This may hint at an altered early-disease awareness of functional changes and underscores the importance of self-report of IADL functioning in addition to collateral report by a study partner.

Using Digital Tools to Advance Alzheimer's Drug Trials During a Pandemic: The EU/US CTAD Task Force.

The 2020 COVID-19 pandemic has disrupted Alzheimer's disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer's Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Item-Level Investigation of Participant and Study Partner Report on the Cognitive Function Index from the A4 Study Screening Data.

BACKGROUND: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. OBJECTIVES: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. DESIGN, SETTING, PARTICIPANTS: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). MEASUREMENTS: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. RESULTS: Independent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p<0.001) and lower education (r=-0.08, p<0.001) of the participant were associated with higher CFI. Highest coincident odds ratios related to Aß+ for both respondents included items assessing whether 'a substantial decline in memory' had occurred in the last year (ORsp= 1.35 [95% CI 1.11, 1.63]; ORp= 1.55 [95% CI 1.34, 1.79]) and whether the participant had 'seen a doctor about memory' (ORsp= 1.56 [95% CI 1.25, 1.95]; ORp =1.71 [95% CI 1.37, 2.12]). For two items, associations were significant for only study partner report; whether the participant 'Repeats questions' (ORsp = 1.30 [95% CI 1.07, 1.57]) and has 'trouble following the news' (ORsp= 1.46[95% CI 1.12, 1.91]). One question was significant only for participant report; 'trouble driving' (ORp= 1.25 [95% CI 1.04, 1.49]). CONCLUSIONS: Elevated Aß is associated with greater reporting of subjective cognitive changes as measured by the CFI in this cognitively unimpaired population. While participants were more likely than study partners to endorse change on most CFI items, unique CFI items were associated with elevated Aß for participants and their study partners, supporting the value of both sources of information in clinical trials.

EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer's Prevention Trials.

At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.