BackgroundResearch has revealed that manifest Alzheimer’s disease (AD) dementia is preceded by preclinical and prodromal phases during which pathology is accumulating but function remains intact. This understanding and concern that disease-modifying interventions initiated at the dementia stage may come too late in the neurodegenerative process to be successful has led to a paradigm shift in AD clinical trials. AD trials now enroll patients with mild cognitive impairment (MCI) and persons with no cognitive symptoms. Trial designs are similar to those enrolling dementia participants. We set out to test the hypothesis that attitudes towards trial design features differ among different potential AD trial populations.MethodsWe sent a survey composed of 37 items assessing specific trial elements to 246 cognitively normal, MCI, and AD dementia participants at the University of California Los Angeles (UCLA) Alzheimer’s Disease Research Center (ADRC), from whom we received 91 responses (37 cognitively normal, 32 MCI, and 22 dementia). To quantify willingness to enroll, we created three composite scenarios by summing responses and fitting proportional odds models with a binary outcome variable for whether patients were highly willing to participate in low-, moderate-, or high-risk and burden trials.ResultsMCI participants less frequently correctly self-identified their diagnoses than those with dementia or normal cognition. Compared to dementia patients, the odds of participating in a low-risk, low-burden trial were 12% lower for MCI patients (odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.23–3.29) and 70% lower (OR = 0.30, 95% CI 0.08–1.09) for cognitively normal participants. With increasing risk and burden, willingness to enroll decreased and the gap in relative willingness between diagnostic groups increased. In the medium-risk, medium-burden scenario, the estimated OR was 0.64 (95% CI 0.17–2.40) for MCI and 0.21 for the cognitively normal (95% CI 0.06–0.77). In the high-risk, high-burden scenario, the estimated OR indicated reduced willingness for MCI (OR = 0.27, 95% CI 0.06–1.15) and cognitively normal respondents (OR = 0.12, 95% CI 0.03–0.54).ConclusionsThese results suggest that AD trials enrolling predementia populations, especially those requiring frequent visits and implementing biomarker testing procedures, may encounter challenges to enrollment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0311-5) contains supplementary material, which is available to authorized users.

Background: Alzheimer's disease (AD) clinical trials require enrollment of a participant and a study partner, whose role includes assessing participant cognitive and functional performance. AD trials now investigate early stages of the disease, when participants are not cognitively impaired. This gives rise to the question of whether study partners or participants provide more information in these trials. Methods: We used data from the AD Cooperative Study Prevention Instrument Project (ADCS-PI) to compare participant and study partner predictions of the participant's current and future cognitive state. We used the Cognitive Function Instrument (CFI) as a measure of evaluation of the participant's cognitive status and the modified ADCS Preclinical Alzheimer's Cognitive Composite (mADCS-PACC) as an objective measure of cognition. Stratifying by cognitive status and study partner type and adjusting for other predictors of the participant's cognitive state, we used random forests along with estimated mean variable importance (eMVI) to assess how well each member of the dyad can predict cognitive state at current and later visits. We also fit linear regression models at each time point and for each scenario. Results: Participants were better at predicting future cognitive status compared to their study partners regardless of study partner type, though the difference between participants and partners was greatest for non-spousal dyads in the lowestperforming quartile. Cross-sectional assessments differed substantially by dyad type. Within the lowest cognitive performance quartile, participants having a non-spousal study partner outperformed their partners in assessing cognition at later times. Spousal partners, in contrast, outperformed participants later in the study in predicting current cognitive performance. Conclusions: These results indicate that participants tend to be better at predicting future cognition compared to their study partners regardless of the study partner type. When assessing current cognition, however, spousal study partners perform better at later time points and non-spousal study partners do not provide as much information regarding participant cognitive state.

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Background: Prodromal Alzheimer's disease (AD) clinical trials enroll patients with Mild Cognitive Impairment (MCI) meeting biomarker criteria, but specific enrollment criteria vary among trials. Methods: We used data from AD Neuroimaging Initiative (ADNI) MCI participants to assess AD biomarker eligibility, variation in trial outcome measures, and statistical power. Results: Most (65%) participants meet eligibility criteria based on low cerebrospinal fluid (CSF) amyloid beta (Aβ). Relative to trials enrolling exclusively based on low CSF Aβ, trials including participants with a high ratio of phosphorylated tau (p-Tau) to Aβ would include an additional 15% of participants. Fewer (34-62%) participants met criteria for Aβ and tau. Differences in clinical and demographic characteristics of modeled trial samples were minimal. Those with low Aβ and high tau showed the greatest change over time on outcome measures. Conclusions: Eligibility rates for prodromal trials vary depending on the specific biomarker criteria, though differences in demographics and the variation associated with outcome measures are minimal. Broadening inclusion criteria beyond amyloid alone may facilitate recruitment but include patients showing slower progression over time. Biomarker criteria selection should be