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Abstract INTRODUCTION To investigate the utility of a new digital tool for measuring everyday functioning in preclinical Alzheimer's disease, we piloted the Assessment of Smartphone Everyday Tasks (ASSET) application. METHODS Forty‐six participants (50.3 ± 27.1 years; 67% female; 20 young unimpaired, 17 old unimpaired, 9 mildly cognitively impaired) completed ASSET 7 times. ASSET comprises two main tasks, simulating a Patient Portal and a Calendar. We assessed ASSET's internal consistency, test–retest reliability, and user experience. RESULTS ASSET main tasks correlated with each other (r = 0.75, 95% confidence interval [CI] = [0.58, 0.86]). Performance on ASSET's Patient Portal related to cognition (r = 0.64, 95% CI = [0.42, 0.79]) and observer ratings of everyday functioning (r = 0.57, 95% CI = [0.24, 0.79]). Test–retest reliability was good (intraclass correlation coefficient = 0.87, 95% CI = [0.77, 0.93]). Most participants rated their experience with ASSET neutrally or positively. DISCUSSION ASSET is a promising smartphone‐based digital assessment of everyday functioning. Future studies may investigate its utility for early diagnosis and evaluation of treatment of Alzheimer's disease.

Abstract The Face Name Associative Memory Exam (FNAME) was introduced into the NIH Toolbox as part of the ARMADA study and establishes normative data for diverse participants, ages 64 to 85+, and proposes cutoff scores between biomarker positive versus negative (+/−) groups. The FNAME was administered to 257 participants across the clinical spectrum with 122 having amyloid biomarkers. Linear regression explored the association between demographics and FNAME and between amyloid (+/−) groups. Receiver operating characteristic curves (ROC) identified performance thresholds that best discriminated between biomarker (+/−) individuals. Lower FNAME scores occurred in males, older ages, Black/African Americans, Hispanics, and biomarker‐positive participants. ROC analyses demonstrated acceptable accuracy (0.73 to 0.77) but only when combined with clinical status. The diagnostic discrimination of amyloid positivity was acceptable but not excellent, suggesting the FNAME may be a better screening indicator of clinical status rather than amyloid deposition in cognitively normal individuals. Normative data are provided.

Abstract Introduction GERAS‐US prospectively characterized clinical and economic outcomes of early symptomatic Alzheimer's disease (AD). Societal cost changes were examined in amyloid‐positive patients with mild cognitive impairment due to AD (MCI) and mild dementia due to AD (MILD). Methods Cognition, function, and caregiver burden were assessed using Mini‐Mental State Examination (MMSE), Cognitive Function Index (CFI), and Zarit Burden Interview, respectively. Costs are presented as least square mean for the overall population and for MCI versus MILD using mixed model repeated measures. Results MMSE score and CFI worsened. Total societal costs (dollars/month) for MCI and MILD, respectively, were higher at baseline ($2430 and $4063) but steady from 6 ($1977 and $3032) to 36 months ($2007 and $3392). Direct non‐medical costs rose significantly for MILD. Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months. Discussion Function and cognition declined in MILD. Non‐medical costs reflect the increasing impact of AD even in its early stages. HIGHLIGHTS In the GERAS‐US study, total societal costs for patients with mild cognitive impairment due to Alzheimer's disease (MCI) and mild dementia due to Alzheimer's disease (MILD) were higher at baseline but steady from 6 to 36 months. Mini‐Mental State Examination (MMSE) and Cognitive Function Index (CFI) worsened; the rate of decline was significant for patients with MILD but not for those with MCI. There was a rise in direct non‐medical costs at 36 months for patients with MILD. Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months. Slowing the rate of disease progression in this early symptomatic population may allow patients to maintain their ability to carry out everyday activities longer.

Abstract Introduction Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory. Methods We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi‐site secondary prevention trial (A4 screen data; mean ±SD: age = 71.3 ±4.7, education = 16.6 ±2.8, 59% women, 96% non‐Hispanic or Latino, 92% White]. Results On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant‐reported mood/anxiety. Discussion Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant‐ and SP‐reported concerns, which may inform trial recruitment and clinical interventions.

Abstract Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n = 3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short‐term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow‐up period provides additional insights into early Alzheimer's disease processes.

Abstract Introduction The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS. Methods Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor‐based, distribution‐based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including the Clinical Dementia Rating—Sum of Boxes, Mini‐Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia. Results All three anchors met criteria for “sufficiently associated” (|r| = 0.4–0.7). Cumulatively, results from anchor‐based and distribution‐based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values. Discussion These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression.

Abstract Introduction We aimed to examine the contribution of subjective cognitive decline (SCD) to reduce the number of β‐amyloid (Aβ) positron emission tomography scans required for recruiting Aβ+ clinically normal individuals in clinical trials. Methods Three independent cohorts (890 clinically normal: 72 yrs ± 6.7; Female: 43.4%; SCD+: 24%; apolipoprotein E [APOE] ε4+: 28.5%; Aβ+: 32%) were used. SCD was dichotomized from one question. Using logistic regression, we classified Aβ+ using the SCD dichotomy, APOEε4, sex, and age. Results SCD increased odds of Aβ+ by 1.58 relative to non‐SCD. Female APOEε4 carriers with SCD exhibited higher odds of Aβ+ (OR = 3.34), whereas male carriers with SCD showed a weaker, opposing effect (OR = 0.37). SCD endorsement reduces the number of Aβ positron emission tomography scans to recruit Aβ+ individuals by 13% and by 9% if APOEε4 status is known. Conclusion SCD helps to classify those with high Aβ, even beyond the substantial effect of APOE genotype. Collecting SCD is a feasible method for targeting recruitment for those likely on the AD trajectory.

Abstract Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a “clinically meaningful outcome” in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19–20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future.

Abstract Introduction Unsupervised digital cognitive testing is an appealing means to capture subtle cognitive decline in preclinical Alzheimer's disease (AD). Here, we describe development, feasibility, and validity of the Boston Remote Assessment for Neurocognitive Health (BRANCH) against in‐person cognitive testing and amyloid/tau burden. Methods BRANCH is web‐based, self‐guided, and assesses memory processes vulnerable in AD. Clinically normal participants (n = 234; aged 50–89) completed BRANCH; a subset underwent in‐person cognitive testing and positron emission tomography imaging. Mean accuracy across BRANCH tests (Categories, Face‐Name‐Occupation, Groceries, Signs) was calculated. Results BRANCH was feasible to complete on participants’ own devices (primarily smartphones). Technical difficulties and invalid/unusable data were infrequent. BRANCH psychometric properties were sound, including good retest reliability. BRANCH was correlated with in‐person cognitive testing (r = 0.617, P

Abstract Introduction To assess the relationship between memory performance defined by the Stages of Objective Memory Impairment (SOMI) system and the Alzheimer's disease (AD) ATN (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) biomarker system. Methods We used data from the Harvard Aging Brain Study cohort to estimate the level of ATN biomarkers: amyloid beta (C‐Pittsburgh compound B‐positron emission tomography [PET]), tau (F‐18–flortaucipir [FTP] PET), and neurodegeneration (magnetic resonance imaging volumetrics). We assessed the cross‐sectional relationship of SOMI classification with global amyloid levels, entorhinal and inferior temporal tau deposition, and hippocampal atrophy. Results Participants with both memory storage and retrieval deficits (SOMI‐3, ‐4) had smaller hippocampal volumes and higher entorhinal and inferior temporal tau burden than participants with no memory impairment (SOMI‐0) or mild retrieval difficulty (SOMI‐1). Amyloid burden did not differ among SOMI stages. Discussion This pilot supports the close relationship between tau pathology and memory impairment across the AD continuum. SOMI may be useful to determine eligibility for randomized controlled trials prior to the assessment of biomarker status.

Abstract Introduction We examined the associations among instrumental activities of daily living (IADL), cortical amyloid, and cognition in cognitively normal (CN) older adults. Methods CN participants screening for the A4 Study (n = 4486) underwent florbetapir (amyloid) positron emission tomography. IADL were assessed using the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument. Separate logistic regression models were run with cortical amyloid or cognition as independent variable and IADL as dependent variable, adjusting for age and sex. Results IADL difficulties were endorsed infrequently (≤16%). Overall IADL and four select IADL item difficulties (“remembering appointments,” “finding belongings,” “following TV programs,” and “remembering current events”) reported by both participant and study partner were significantly associated with greater amyloid burden and worse cognition. Discussion Although IADL deficits were infrequent in this CN cohort, greater participant and study partner report of overall IADL deficits and subtle difficulties in specific IADL items were associated with mildly higher amyloid burden and worse cognition.

Abstract Introduction We determine whether diminished Learning Over Repeated Exposures (LORE) identifies subtle memory decrements in cognitively unimpaired (CU) older adults with Alzheimer's disease (AD) biomarker burden. Methods Ninety‐four CU participants (mean age = 77.6 ± 5.02) completed a challenging associative memory test, at home, monthly, for up to 1 year (mean = 9.97 months) on a study‐issued iPad. Learning curves for face‐name memory were computed for two versions completed monthly: same face‐name pairs (A‐A‐A) and alternate face‐name pairs (B‐C‐D). Positron emission tomography (PET) imaging characterized global amyloid (Pittsburgh Compound‐B (PiB); amyloid beta (Aβ)+/−) and regional tau burden (flortaucipir). Results Diminished LORE for same (but not alternate) face‐name pairs was associated with greater amyloid and tau burden. Aβ+/− group differences for same face‐name pairs emerged by the fourth exposure and was of medium‐to‐large magnitude (Cohen's d = 0.66; 95% confidence interval [CI] = 0.25‐1.08). Discussion Subtle decrements in learning related to AD pathological burden in CU are detectable over short time‐intervals (ie, months). Implications for prevention trial design are discussed.

Abstract Introduction Alzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories remaining more intact than recent memories. It is unclear whether this temporal pattern is observable in clinically normal adults with amyloid pathology (i.e. preclinical AD). Methods Participants were asked to recall the names of famous figures most prominent recently (famous after 1990) and remotely (famous from 1960–1980) and were provided with a phonemic cue to ensure that memory failure was not purely due to verbal retrieval weaknesses. In addition, participants identified line drawings of objects. Clinically normal older adults (n = 125) were identified as amyloid β positive or negative (Aβ+/−) using Pittsburgh compound B positron emission tomography. The relationship between Aβ+/− and recall of remote and recent famous face‐names and objects was examined using repeated measures analyses and general linear models controlling for demographics and media usage. Results When provided with a phonemic cue, Aβ+ participants recalled the names of fewer recent famous faces compared with Aβ− participants. However, recall of remote famous face‐names and objects did not differ by Aβ group. Discussion Relative sparing of remotely learned information compared with recently learned information is (1) detectable in the preclinical stages of AD and (2) related to amyloid pathology. Both this temporal gradient and assessment of person‐centered rather than object‐centered semantic information may be particularly meaningful for tracking early memory changes in the AD trajectory.