Abstract INTRODUCTION Secondary prevention trials targeting preclinical Alzheimer's disease (AD) require clinical outcome assessments (COAs) that are sensitive to subtle decline that might be found in the cognitively unimpaired population typically enrolled in these trials. The recently completed Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) trial is an opportunity to explore the performance of commonly applied COAs in the preclinical AD population. METHODS The performance of COAs was compared using power calculations informed by data from the placebo arm of the A4 trial alone ( N = 583), and through a cross‐cohort analysis incorporating data from participants in the companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study ( N = 538). Outcomes included the Preclinical Alzheimer's Cognitive Composite (PACC), the Clinical Dementia Rating Sum of Boxes (CDR‐SB), the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADL‐PI), and the Cognitive Function Instrument (CFI). RESULTS The PACC and its component neuropsychological tests did not meaningfully decline over the first 168 weeks of the trial, compromising their utility as trial endpoints. In contrast, the CDR‐SB and the ADL‐PI declined monotonically. Based on the progression observed in A4 alone, a trial using the CDR‐SB endpoint would require a fraction of the participants required for a commonly used neuropsychological endpoint. DISCUSSION These findings help inform the selection of clinical endpoints for secondary prevention trials, and highlight potential limitations of cognitive performance tests in the earliest stages of AD. We found that practice effects on the PACC and its component tests were present despite the use of alternating test forms, reducing the effectiveness of these instruments in this population and motivating future exploration of the effectiveness of alternate clinical endpoints.
Abstract Introduction Real‐world evidence comparing the functional and cognitive outcomes associated with commonly prescribed second‐generation antipsychotics (SGAs) in long‐term care (LTC) residents with Alzheimer disease (AD) is limited. Methods We emulated target trials using linked LTC Data Cooperative and Medicare data. A total of 17,766 eligible new users initiating risperidone, quetiapine, olanzapine, or aripiprazole were compared under an intention‐to‐treat framework using inverse probability of treatment weighting and weighted generalized estimating equations. Outcomes were 12‐month trajectories of Activities of Daily Living (ADL) and Brief Interview for Mental Status (BIMS). Results ADL trajectories were similar across SGAs. In BIMS trajectory, quetiapine was associated with a modestly greater decline ( β = −0.203, 95% confidence interval [CI] −0.380 to −0.027) compared with aripiprazole. Age modified several comparative treatment effects, particularly for BIMS. Findings were consistent across sensitivity analyses. Discussion Long‐term functional and cognitive outcomes were broadly comparable across commonly prescribed SGAs. Age‐related heterogeneity in comparative treatment effects warrants further investigation.
Abstract INTRODUCTION Anti‐amyloid therapies (AATs) for Alzheimer's disease (AD) offer modest slowing of cognitive decline but involve meaningful risks, burdens, and uncertainty. Decisions about AAT are preference sensitive and optimally guided by shared decision making (SDM), yet little is known about how these conversations unfold in real‐world clinical practice. METHODS We conducted an exploratory qualitative content analysis of audio‐recorded AAT counseling encounters in neurology clinics at two academic medical centers. Participants included neurology clinicians, patients with mild cognitive impairment or mild dementia due to AD, and care partners. We examined how clinicians presented options, benefits, risks, and burdens; elicited patient values and preferences; assessed understanding; and engaged patients and care partners. RESULTS We analyzed 10 encounters involving 9 patients and 5 clinicians; 8 patients had a care partner present. Encounters occurred at different stages of decision making, including pre‐decision visits and visits in which a treatment decision was made. Clinicians consistently explained AAT mechanisms using action‐oriented language, emphasized modest benefits, and discussed amyloid‐related imaging abnormalities, magnetic resonance imaging monitoring as a safety net, and treatment logistics. However, communication framing varied. Some clinicians used optimistic framing that may have shaped treatment perceptions, while explicit discussion of not pursuing AAT as a valid option was rare. Open‐ended exploration of values and goals varied and occurred more often in pre‐decision encounters, whereas visits closer to treatment decisions focused on treatment selection and logistics. Assessment of treatment understanding ranged from open‐ended teach‐back, which revealed misunderstandings in some cases, to closed‐ended checks. Clinicians also varied in how they balanced patient and care partner participation. DISCUSSION Although clinicians consistently addressed core medical information about AAT, variation in framing, values elicitation, teach‐back, presentation of alternatives, and patient–care partner engagement may shape AAT decision making. Communication strategies that explicitly present options, connect potential outcomes to patient priorities, and reinforce understanding may support balanced, values‐aligned SDM.
