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BackgroundWith the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.Methods and findingsWe included cognitively unimpaired individuals aged 60-75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer's Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60-64, 65-69, 70-75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60-64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65-69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70-75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80-85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%-38.45% at age 60-64 y, 30.76%-40.26% at 65-69 y, and 33.3%-35.17% at 70-75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.ConclusionsEstimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies-with implications for informed consent and design for clinical trials targeting high-risk individuals.

INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE‐1 inhibitor umibecestat in cognitively unimpaired 60‐ to 75‐year‐old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty‐five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow‐up Aβ positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: −0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid‐related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. Highlights: This was the first amyloid‐lowering prevention trial in persons at genetic risk of late‐onset Alzheimer's disease (AD).Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial.CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes.CAD106 was generally safe and well tolerated, with only three amyloid‐related imaging abnormality cases (one symptomatic).Such an approach deserves further evaluation in larger AD prevention trials. [ABSTRACT FROM AUTHOR]

To identify factors that predict COVID-19 vaccination refusal and show how expectancies affect vaccination acceptance for non-vaccinated adults, we used a monthly repeated cross-sectional sample from June/2021 to October/2021 to collect data on vaccination behaviors and predictor variables for 2,116 US adults over 50 years of age. Selection bias modeling – which is required when data availability is a result of behavioral choice – predicts two outcomes: (1) no vaccination vs. vaccination for the entire sample and (2) the effects of expectancy indices predicting vaccination Refuser vs. vaccination Accepters for the unvaccinated group. Vaccine refusers were younger and less educated, endorsed common misconceptions about the COVID-19 epidemic, and were Black. Vaccination expectancies were related to vaccination refusal in the unvaccinated eligible group: negative expectancies increased vaccine refusal, while positive expectancies decreased it. We conclude that behavior-related expectancies (as opposed to more stable psychological traits) are important to identify because they are often modifiable and provide a point of intervention, not just for COVID-19 vaccination acceptance but also for other positive health behaviors. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's‐focused participant recruitment registries are tools for accelerating enrollment into studies, however, registry members are primarily White women. METHODS: We conducted a national online survey of 1501 adults ages 50–80, oversampling for Black and Hispanic/Latino respondents, assessing intention to join a generic "brain health" registry and to join a registry that required specific tasks. RESULTS: Intention to join a registry was low (M 3.48, SD 1.77), and lower than intention to join a registry requiring specific tasks. Intention was greatest for registries requiring completing surveys (M 4.70, SD 1.77). Differences in intention were primarily between White women and Black women; differences between other groups were limited to specific tasks required. DISCUSSION: The results indicate uncertainty about what a registry is, its purpose, and/or the concept of "brain health." Using the Reasoned Action Approach (RAA) to develop evidence‐based outreach messages describing a registry and required tasks may increase diversity. [ABSTRACT FROM AUTHOR]

Clinical trials for Alzheimer's 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 Alzheimer's 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 panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD. [ABSTRACT FROM AUTHOR]

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi‐step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much‐needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. Highlights: We discuss lessons learned on capturing cognitive changes in predementia stages of AD.We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials.We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials. [ABSTRACT FROM AUTHOR]

Introduction: Females may have greater susceptibility to Alzheimer's disease (AD)‐pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively‐unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers and non‐carriers. Methods: We analyzed baseline data from 167 mutation carriers and 75 non‐carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir‐ and fludeoxyglucose‐PET, MRI based hippocampal volume and cognitive testing. Results: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. Discussion: Our findings suggest that, among cognitively‐unimpaired individuals at genetic risk for autosomal‐dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex‐specific differences in autosomal‐dominant AD is key to elucidating mechanisms of AD risk and resilience. [ABSTRACT FROM AUTHOR]