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BackgroundGreater 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.ObjectivesTo 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, participantsFour 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).MeasurementsPrior 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.ResultsIndependent 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

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data., Competing Interests: Conflict of interest Paul Maruff is a full-time employee of Cogstate Ltd. Samuel N. Lockhart is a full time employee of Invicro LLC. SCJ has served in the past three years as a consultant to ALZPath and Enigma Biomedical.

Importance: Depressive symptoms in older adults may be a harbinger of Alzheimer disease (AD), even in preclinical stages. It is unclear whether worsening depressive symptoms are manifestations of regional distributions of core AD pathology (amyloid) and whether cognitive changes affect this relationship., Objective: To evaluate whether increasing depressive symptoms are associated with amyloid accumulation in brain regions important for emotional regulation and whether those associations vary by cognitive performance., Design, Setting, and Participants: Participants from the Harvard Aging Brain Study, a longitudinal cohort study, underwent annual assessments of depressive symptoms and cognition alongside cortical amyloid positron emission tomography (PET) imaging at baseline and every 2 to 3 years thereafter (mean [SD] follow-up, 8.6 [2.2] years). Data collection was conducted from September 2010 to October 2022 in a convenience sample of community-dwelling older adults who were cognitively unimpaired with, at most, mild baseline depression. Data were analyzed from October 2022 to December 2023., Main Outcomes and Measures: Depression (Geriatric Depression Scale [GDS]-30-item), cognition (Preclinical Alzheimer Cognitive Composite-5 [PACC]), and a continuous measure of cerebral amyloid (Pittsburgh compound B [PiB] PET) examined in a priori-defined regions (medial orbitofrontal cortex [mOFC], lateral orbitofrontal cortex, middle frontal cortex [MFC], superior frontal cortex, anterior cingulate cortex, isthmus cingulate cortex [IC], posterior cingulate cortex, and amygdala). Associations between longitudinal GDS scores, regional amyloid slopes, and PACC slopes were assessed using linear mixed-effects models., Results: In this sample of 154 individuals (94 [61%] female; mean [SD] age, 72.6 [6.4] years; mean (SD) education, 15.9 [3.1] years), increasing PiB slopes in the bilateral mOFC, IC, and MFC were associated with increasing GDS scores (mOFC: β = 11.07 [95% CI, 5.26-16.87]; t = 3.74 [SE, 2.96]; P = .004; IC: β = 12.83 [95% CI, 5.68-19.98]; t = 3.51 [SE, 3.65]; P = .004; MFC: β = 9.22 [95% CI, 2.25-16.20]; t = 2.59 [SE, 3.56]; P = .03). Even with PACC slope as an additional covariate, associations remained significant in these regions., Conclusions and Relevance: In this cohort study of cognitively unimpaired older adults with, at most, mild baseline depressive symptoms, greater depressive symptoms over time were associated with amyloid accumulation in regions associated with emotional control. Furthermore, these associations persisted in most regions independent of cognitive changes. These results shed light on the neurobiology of depressive symptoms in older individuals and underscore the importance of monitoring for elevated mood symptoms early in AD.

Importance: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes., Objective: To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults., Design, Setting, and Participants: This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded., Main Outcomes and Measures: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite., Results: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition., Conclusions and Relevance: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults., Design: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year., Setting: Community-dwelling participants assessed at research visits in an academic medical center., Participants: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6)., Measurements: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment., Results: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aβ, we observed an association between AES-I and inferior temporal tau., Conclusions: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy., Competing Interests: DISCLOSURES Dr. Gad Marshall receives salary support from NIH/NIA R01 AG071074, R01 AG067021, R01 AG053184, R21 AG064413, R42 AG069629, and R21 AG070877. Dr. Marshall also receives salary support for serving as site principal investigator for clinical trials funded by Eisai Inc., Eli Lilly and Company, and Genentech. These relationships are not related to the content in the manuscript. Dr. Catherine Munro has a research fellowship from the Alzheimer's Association (AARF-23-1150240). This relationship is not related to the content in the manuscript. Dr. Jennifer Gatchel receives salary support from NIH/NIA K23AG05880, NIH/NIA R01AG07819. She is paid from the MEDVAMC. These relationships are not relevant to the content of the manuscript. Dr. Kathryn Papp receives support in the form of consulting fees from Cogstate and Novoic. These relationships are not relevant to the content of the manuscript. Dr. Hyun-Sik Yang receives salary support from NIH/NIA K23AG062750 and NIH/NIA R01AG080667. This relationship is not relevant to the content of the manuscript. Zoe Katz received support from R01AG065234 in the last 36 months. This relationship is not relevant to the content of the manuscript. Dr. Dorene Rentz receives payments from AAAS and IMPACT AD for lectures/speakership events. She also participates on a Data Safety Monitoring/Advisory Board for Washington University, Northwestern, UC-Davis, and Boston University. These relationships are not relevant to the content of the manuscript. Dr. Keith Johnson receives support from the following: NIH-NIA 5R01AG046396-05. Moreover, he is paid as a consultant for Merck and Novartis. These relationships are not relevant to the content of the manuscript. Dr. Reisa Sperling receives support from the NIH (P01AG036694) as funding to institution. She also has the following grants/contracts: Alzheimer's Association (to institution), NIA (to institution), GHR foundation (to institution), Eli Lilly (research funding on clinical trial sites), Eisai (research funding on clinical trial sites). Moreover, she is paid directly as a consultant for the following companies: AC Immunce, Acumen, Alector, Alnylam, Genetech, Janssen, JOMDD, Nervgen, Neuraly, Neurocentria, Oligomerix, Prothena, Renew, Shionogi, Vigil Neuroscience, Ionis, Vaxxinity, Bristol Myers Squibb. These relationships are not related to the content in the manuscript. Dr. Yakeel Quiroz receives support from the following grants/contracts: Alzheimer's Association, NIA, Massachusetts General Hospital ECOR which are all paid to her institution. She also has payment support from Biogen. These relationships are not related to the content in the manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Background: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR., Methods: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women)., Results: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline., Conclusion: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity., (© 2024. The Author(s).)

Background and Objectives: Self-reported cognitive decline is an early behavioral manifestation of Alzheimer disease (AD) at the preclinical stage, often believed to precede concerns reported by a study partner. Previous work shows cross-sectional associations with β-amyloid (Aβ) status and self-reported and study partner-reported cognitive decline, but less is known about their associations with tau deposition, particularly among those with preclinical AD., Methods: This cross-sectional study included participants from the Anti-Amyloid Treatment in Asymptomatic AD/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies (N = 444) and the Harvard Aging Brain Study and affiliated studies (N = 231), which resulted in a cognitively unimpaired (CU) sample of individuals with both nonelevated (Aβ-) and elevated Aβ (Aβ+). All participants and study partners completed the Cognitive Function Index (CFI). Two regional tau composites were derived by averaging flortaucipir PET uptake in the medial temporal lobe (MTL) and neocortex (NEO). Global Aβ PET was measured in Centiloids (CLs) with Aβ+ >26 CL. We conducted multiple linear regression analyses to test associations between tau PET and CFI, covarying for amyloid, age, sex, education, and cohort. We also controlled for objective cognitive performance, measured using the Preclinical Alzheimer Cognitive Composite (PACC)., Results: Across 675 CU participants (age = 72.3 ± 6.6 years, female = 59%, Aβ+ = 60%), greater tau was associated with greater self-CFI (MTL: β = 0.28 [0.12, 0.44], p < 0.001, and NEO: β = 0.26 [0.09, 0.42], p = 0.002) and study partner CFI (MTL: β = 0.28 [0.14, 0.41], p < 0.001, and NEO: β = 0.31 [0.17, 0.44], p < 0.001). Significant associations between both CFI measures and MTL/NEO tau PET were driven by Aβ+. Continuous Aβ showed an independent effect on CFI in addition to MTL and NEO tau for both self-CFI and study partner CFI. Self-CFI (β = 0.01 [0.001, 0.02], p = 0.03), study partner CFI (β = 0.01 [0.003, 0.02], p = 0.01), and the PACC (β = -0.02 [-0.03, -0.01], p < 0.001) were independently associated with MTL tau, but for NEO tau, PACC (β = -0.02 [-0.03, -0.01], p < 0.001) and study partner report (β = 0.01 [0.004, 0.02], p = 0.002) were associated, but not self-CFI (β = 0.01 [-0.001, 0.02], p = 0.10)., Discussion: Both self-report and study partner report showed associations with tau in addition to Aβ. Additionally, self-report and study partner report were associated with tau above and beyond performance on a neuropsychological composite. Stratification analyses by Aβ status indicate that associations between self-reported and study partner-reported cognitive concerns with regional tau are driven by those at the preclinical stage of AD, suggesting that both are useful to collect on the early AD continuum.

Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults., Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education., Results: Amyloid [unstandardized partial regression coefficient estimate (β) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [β = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time., Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dubbelman, Diez, Gonzalez, Amariglio, Becker, Chhatwal, Gatchel, Johnson, Locascio, Udeogu, Wang, Papp, Properzi, Rentz, Schultz, Sperling, Vannini and Marshall.)

Objective: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments., Methods: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60-91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ- using positron emission tomography with 11C Pittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years., Results: At the cross-section, there were no statistically significant differences in performance between Aβ+/- participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ- participants (Cohen d = 0.49, 95% confidence interval = 0.10-0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001)., Interpretation: Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507-517., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning over repeated evaluations on participants' own devices. This provides the opportunity to derive individual multiday learning curve scores over short intervals. Here, we report feasibility, reliability, and validity, of a 7-day cognitive battery from the Boston Remote Assessment for Neurocognitive Health (Multiday BRANCH), an unsupervised web-based assessment., Method: Multiday BRANCH was administered remotely to 181 cognitively unimpaired older adults using their own electronic devices. For 7 consecutive days, participants completed three tests with associative memory components (Face-Name, Groceries-Prices, Digit Signs), using the same stimuli, to capture multiday learning curves for each test. We assessed the feasibility of capturing learning curves across the 7 days. Additionally, we examined the reliability and associations of learning curves with demographics, and traditional cognitive and subjective report measures., Results: Multiday BRANCH was feasible with 96% of participants completing all study assessments; there were no differences dependent on type of device used ( t = 0.71, p = .48) or time of day completed ( t = -0.08, p = .94). Psychometric properties of the learning curves were sound including good test-retest reliability of individuals' curves (intraclass correlation = 0.94). Learning curves were positively correlated with in-person cognitive tests and subjective report of cognitive complaints., Conclusions: Multiday BRANCH is a feasible, reliable, and valid cognitive measure that may be useful for identifying subtle changes in learning and memory processes in older adults. In the future, we will determine whether Multiday BRANCH is predictive of the presence of preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Objective: To investigate whether intraindividual variability (IIV) in reaction time (RT) over monthly administered cognitive tasks is increased in cognitively unimpaired older adults who are at risk for cognitive decline, and whether this is independent of mean RT performance., Method: N = 109 cognitively unimpaired individuals (age 77.4 ± 5.0, 61.5% female, Mini-Mental State Examination 29.1 ± 1.3) from the Harvard Aging Brain Study completed the self-administered Computerized Cognitive Composite (C3) monthly at home for up to 1 year (12.7 ± 3.2 C3 assessments). Baseline C3 assessment coincided with routine in-clinic visits, including amyloid and tau positron emission tomography imaging and standardized cognitive testing, with cognitive testing repeated annually (1.6 ± 1.2 years follow-up). The C3 includes two simple RT tasks and two complex RT tasks. IIV estimates were derived by computing intraindividual standard deviations on residual RT scores after regressing out age and session order effects. Cross-sectional associations of IIV with cognition (global cognition, memory, executive functions [EF], processing speed) and amyloid and tau burden were examined using linear regression analyses correcting for demographics and mean RT. The association between IIV and cognitive decline was assessed using linear mixed models correcting for demographic factors, mean RT, and amyloid burden., Results: After adjusting for mean RT, increased IIV on complex RT tasks was independently associated with worse EF performance (β = -0.10, 95% CI [-.16, -0.03], p = .004), greater inferior-temporal tau deposition (β = 0.18, 95% CI [0.02, 0.34], p = .024), and faster cognitive decline in those with elevated amyloid (β = -0.62, 95% CI [-1.18, -0.06], p = .033)., Conclusions: Increased variability in monthly RT may reflect subtle EF deficits and provide unique information about short-term cognitive decline in preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer's disease related pathology and neurodegeneration in smaller cohort studies., Objectives: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ)., Design: Longitudinal mixed., Setting: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study., Participants: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive)., Measurements: Global cognitive performance (Preclinical Alzheimer's Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version., Results: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline., Conclusions: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline., Competing Interests: All authors confirm that they do not have conflicts of interest pertinent to this manuscript.

Background: The Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period., Objectives: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study., Design: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally., Setting: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States., Participants: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab., Measurements: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined., Results: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile., Conclusion: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load., Competing Interests: REA received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437). JDG reports funding from NIA, the Alzheimer’s Association, BrightFocus Foundation, Eli Lilly, Biogen, Genentech, and Eisai. He has provided consulting to SiteRx and received personal payments for editorial service to Alzheiemer’s and Dementia. GAM was a site principal investigator for A4, has received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437), has received salary support from Eisai Inc. and Eli Lilly and Company for serving as a site principal investigator for clinical trials, and has received payments for serving as a consultant for Ono Pharma USA, Inc. DMR received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437) and has receive payment or honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) course, Grand Rounds and External Advisory Boards from the University of California, Washington University, Boston University and Northwestern as well as travel support to ACTC meetings, to University of California Advisory Board Meeting and Washington University Advisory Board Meeting. MCD reports that his spouse is a full-time employee of Janssen, and he has served as a consultant to Roche. AL has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. PAS has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. RAS reports grant support from Eisai, and Eli Lilly and reported serving as a consultant for AbbVie, AC Immune, Alector, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Background: Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer's disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid-hallmarks of AD pathology., Objectives: This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time., Design: Participants were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument-Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline)., Setting: Multi-center international cohort study., Participants: Sample size was 507-322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data., Measurements: Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons., Results: Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03)., Conclusions: Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.

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., Competing Interests: G.A.M. is a senior associate editor for this journal but was not involved in the journal's peer‐review process nor had access to any information regarding its peer‐review. The other authors report no conflicts of interest pertaining to this manuscript. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The associations between subjective cognitive decline (SCD), cognition, and amyloid were explored across diverse participants in the A4 study., Methods: Five thousand one hundred and fifty-one non-Hispanic White, 262 non-Hispanic Black, 179 Hispanic-White, and 225 Asian participants completed the Preclinical Alzheimer Cognitive Composite (PACC), self- and study partner-reported Cognitive Function Index (CFI). A subsample underwent amyloid positron emission tomography ( 18 F-florbetapir) (N = 4384). We examined self-reported CFI, PACC, amyloid, and study partner-reported CFI by ethnoracial group., Results: The associations between PACC-CFI and amyloid-CFI were moderated by race. The relationships were weaker or non-significant in non-Hispanic Black and Hispanic White groups. Depression and anxiety scores were stronger predictors of CFI in these groups. Despite group differences in the types of study partners, self- and study partner-CFI were congruent across groups., Discussion: SCD may not uniformly relate to cognition or AD biomarkers in different ethnoracial groups. Nonetheless, self- and study partner-SCD were congruent despite differences in study partner type. Highlights Association between SCD and objective cognition was moderated by ethnoracial group. Association between SCD and amyloid was moderated by ethnoracial group. Depression and anxiety were stronger predictors of SCD in Black and Hispanic groups. Study-partner and self-reported SCD are congruent across groups. Study-partner report was consistent despite difference in study partner types., (© 2023 the Alzheimer's Association.)

Background: Emerging difficulty performing cognitively complex everyday tasks, or 'instrumental activities of daily living' (IADL) may be an early clinical sign of Alzheimer's disease (AD). We aimed to investigate how changes over time in everyday functioning relate to cerebral tau burden across the AD clinical spectrum., Methods: We included 581 participants (73.9 ± 7.6 years old; 52% female) from the Alzheimer's Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247). We analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions in mixed-effects models. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). We additionally investigated tau-PET adjusted for, as well as interacting with, amyloid-β., Results: Greater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning. These findings remained when adjusting for baseline global cortical amyloid-β; amyloid-β itself was only associated with change over time in FAQ scores when tau was not included in the model. When stratifying by diagnostic group, most associations between tau and everyday functioning, adjusted for amyloid-β, were present only in the symptomatic group., Conclusions: The rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid-β, specifically in cognitively symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease., (© 2023. The Author(s).)

Objective: Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies., Method: We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies., Results: We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change., Conclusions: This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objectives: Studies are increasingly examining research questions across multiple cohorts using data from the preclinical Alzheimer cognitive composite (PACC). Our objective was to use modern psychometric approaches to develop a harmonized PACC., Method: We used longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohorts ( n = 2,712). We further demonstrated our method with the Anti-Amyloid Treatment of Asymptomatic Alzheimer's Disease (A4) Study prerandomized data ( n = 4,492). For the harmonization method, we used confirmatory factor analysis (CFA) on the final visit of the longitudinal cohorts to determine parameters to generate latent PACC (lPACC) scores. Overlapping tests across studies were set as "anchors" that tied cohorts together, while parameters from unique tests were freely estimated. We performed validation analyses to assess the performance of lPACC versus the common standardized PACC (zPACC)., Results: Baseline (BL) scores for the zPACC were centered on zero, by definition. The harmonized lPACC did not define a common mean of zero and demonstrated differences in baseline ability levels across the cohorts. Baseline lPACC slightly outperformed zPACC in the prediction of progression to dementia. Longitudinal change in the lPACC was more constrained and less variable relative to the zPACC. In combined-cohort analyses, longitudinal lPACC slightly outperformed longitudinal zPACC in its association with baseline β-amyloid status., Conclusions: This study proposes procedures for harmonizing the PACC that make fewer strong assumptions than the zPACC, facilitating robust multicohort analyses. This implementation of item response theory lends itself to adapting across future cohorts with similar composites. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical., Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults., Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid., Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone., Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample ( n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging ( n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21-0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59-0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden ( r = -0.20, 95% CI [-0.38 - -0.01], p = 0.049) and tau deposition in the entorhinal cortex ( r = -0.38, 95% CI [-0.54 - -0.19], p < 0.001) and inferior-temporal lobe ( r = -0.23, 95% CI [-0.41 - -0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84-0.98]), which was better than baseline C3 ( p < 0.001) and baseline PACC-5 scores ( p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD., Competing Interests: RS receives research funding from NIA, Alzheimer's Association, Eli Lilly and Co., and Eisai. She has served as a consultant to AC Immune, Alyn Cytox, Janssen, Neurocentria, Roche, Prothena, and Shionogi but not directly relevant to this study. MY receives research funding from NIA and NIMH, served as a consultant for Pfizer, Eisai, Cognito Therapeutics, Curasen Therapeutics, BPT Pharma and Dart Neuroscience, and is co-founder of Enthorin Therapeutics and Augnition Labs, none of which are directly relevant to this study. PM is employed full time by Cogstate Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jutten, Rentz, Fu, Mayblyum, Amariglio, Buckley, Properzi, Maruff, Stark, Yassa, Johnson, Sperling and Papp.)

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., Competing Interests: G. Reynolds has nothing to disclose.

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., Competing Interests: MAD and JSS have nothing to disclose. APS has consulted for Janssen, Biogen, Qynapse, and NervGen. DMR has served as a consultant for Eli Lilly, Biogen Idec, Digital Cognition Technologies, and serves as a member of the Scientific Advisory Board for Neurotrack. REA has nothing to disclose. SAMS has provided consultancy services in the past 2 years for Nutricia and Takeda, and has received license fees from Green Valley, VtV Therapeutics, Alzheon, Vivoryon and Roche, as well as honoraria from Boehringer and Toyama. All funds were paid to her institution. RAS has served as a paid consultant for AC Immune, Alynlam, Cytox, Genentech, Janssen, Neurocentria, Prothena, and Roche. She has received research support as an investigator for Eli Lilly, Janssen and Eisai Alzheimer disease clinical trials. KAJ has served as paid consultant for Bayer, GE Healthcare, Janssen Alzheimer’s Immunotherapy, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, ISIS Pharma, AZTherapy, GEHC, Lundberg, and Abbvie. He is a site coinvestigator for Eli Lilly/Avid, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer’s Immunotherapy and Pfizer. GAM has received research salary support for serving as site principal investigator for clinical trials funded by Eisai Inc., Eli Lilly and Company, and Genentech. These relationships are not related to the content in the manuscript.

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., Competing Interests: E.G. receives a small royalty for commercial use of the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT+IR). The test is available at no cost to researchers and clinicians. The Albert Einstein College of Medicines holds the copyright for the test. R.B.L. serves as consultant, advisory board member, or has received honoraria or research support from AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy's Laboratories (Promius), electroCore, Eli Lilly, GlaxoSmithKline, Grifols, Lundbeck, Merck, Novartis, Teva, Vector, and Vedanta Research. He receives royalties from Wolff's Headache, 8th edition (Oxford University Press, 2009), and Informa. He holds stock/options in Biohaven and CntrlM. D.M.R. receives consulting and scientific advisory board fees from Digital Cognition Technologies, Biogen Idec, and Neurotrack. R.A.S. receives clinical trial research support from Eli Lilly and Co. and Eisai. She has received consulting fees from AC Immune, Acumen, Genentech, Janssen, Cytox, Prothena, Renew, Alnylam, Neuraly, and Neurocentria. K.A.J. has received consulting fees from AC Immune, AZTherapies, Genentech, Janssen, Takeda, and Novartis. D.M.R. receives consulting and scientific advisory board fees from Digital Cognition Technologies, Biogen Idec and Neurotrack., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Importance: Detecting cognitive decline earlier among older adults can facilitate enrollment in clinical trials and early interventions. Clinical notes in longitudinal electronic health records (EHRs) provide opportunities to detect cognitive decline earlier than it is noted in structured EHR fields as formal diagnoses., Objective: To develop and validate a deep learning model to detect evidence of cognitive decline from clinical notes in the EHR., Design, Setting, and Participants: Notes documented 4 years preceding the initial mild cognitive impairment (MCI) diagnosis were extracted from Mass General Brigham's Enterprise Data Warehouse for patients aged 50 years or older and with initial MCI diagnosis during 2019. The study was conducted from March 1, 2020, to June 30, 2021. Sections of notes for cognitive decline were labeled manually and 2 reference data sets were created. Data set I contained a random sample of 4950 note sections filtered by a list of keywords related to cognitive functions and was used for model training and testing. Data set II contained 2000 randomly selected sections without keyword filtering for assessing whether the model performance was dependent on specific keywords., Main Outcomes and Measures: A deep learning model and 4 baseline models were developed and their performance was compared using the area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC)., Results: Data set I represented 1969 patients (1046 [53.1%] women; mean [SD] age, 76.0 [13.3] years). Data set II comprised 1161 patients (619 [53.3%] women; mean [SD] age, 76.5 [10.2] years). With some overlap of patients deleted, the unique population was 2166. Cognitive decline was noted in 1453 sections (29.4%) in data set I and 69 sections (3.45%) in data set II. Compared with the 4 baseline models, the deep learning model achieved the best performance in both data sets, with AUROC of 0.971 (95% CI, 0.967-0.976) and AUPRC of 0.933 (95% CI, 0.921-0.944) for data set I and AUROC of 0.997 (95% CI, 0.994-0.999) and AUPRC of 0.929 (95% CI, 0.870-0.969) for data set II., Conclusions and Relevance: In this diagnostic study, a deep learning model accurately detected cognitive decline from clinical notes preceding MCI diagnosis and had better performance than keyword-based search and other machine learning models. These results suggest that a deep learning model could be used for earlier detection of cognitive decline in the EHRs.

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  < .001). Lower BRANCH score was associated with greater amyloid ( r  = -0.205, P  = .007) and entorhinal tau ( r  = -0.178, P  = .026)., Discussion: BRANCH reliably captures meaningful cognitive information remotely, suggesting promise as a digital cognitive marker sensitive early in the AD trajectory., Competing Interests: A. Samaroo, H.C. Chou, O.R. Schneider, D. Soberanes, M. Properzi, J. Burke, R. Kumar, S. Hsieh, N. Snyder, A. Schultz, Iván García‐Magariño, R. Buckley, Y. Quiroz, and R. Amariglio report no disclosures relevant to this manuscript. K. Papp has served as a paid consultant for Biogen and Digital Cognition Technologies. G. Marshall has served as a paid consultant for Grifols Shared Services North America, Inc. and Eisai Inc. He has received honoraria/payments from Miller Medical, South Shore Hospital, and Metrowest Medical Center. D. Rentz has served as a paid consultant for Biogen, Digital Cognition Technologies, Eli Lilly, and Janssen. R. Sperling has received honoraria from Shionogi, Genentech, Oligomerix, Inc., Cytox, Prothena, Acumen, JOMDD, Renew, Alnylam Pharmaceuticals, Neuraly, Janssen, Neurocentria, AC Immune, Biogen, Eisai, Roche, and Takeda Pharmaceuticals. K. Johnson has received consulting fees from Novartis and Cerveau., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging - Alzheimer's Association (NIA-AA) research framework., Method: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models., Results: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = -.58, p < .001). Word List Delayed Recall (β = -.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = -1.13, p < .001) and 4 (β = -2.23, p < .001)., Conclusions: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.

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., Competing Interests: A. Samaroo, R. Amariglio, S. Burnham, P. Sparks, M. Properzi, A. Schultz, and R. Buckley have no disclosures to report. D. Rentz has served as a consultant for Eli Lilly, Biogen Idec, and Lundbeck Pharmaceuticals, and serves as a member of the Scientific Advisory Board for Neurotrack. R.A. Sperling has received research funding from the NIH, Alzheimer's Association, and Eli Lilly for this research. She has served as a consultant for AC Immune, Biogen, Eisai, Janssen, Neurocentria, and Roche.  K. Johnson has served as a consultant to Biogen, Janssen, and Novartis. K. Papp has served as a consultant for Biogen Idec and Digital Cognition Technologies., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia., Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau., Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument -Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age, sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates., Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p < 0.001; inferior temporal: p < 0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p < 0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p < 0.001; and amyloid and supramarginal tau interaction: p = 0.002)., Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

Objective: The Face-Name Associative Memory Exam (FNAME) has been used to detect subtle cognitive changes in clinically normal older adults at increased risk for Alzheimer's disease. FNAME assesses learning and delayed recall for face-name pairs. The aim of this study is to introduce a Latin American Spanish version of the FNAME (LAS-FNAME), examine its psychometric properties, and provide preliminary normative data in a sample of clinically normal, Spanish-speaking individuals from Antioquia, Colombia., Method: 59 clinically-normal individuals (71% females) were recruited by the Grupo de Neurociencias in Antioquia (Colombia). Age ranged from 27 to 82 years ( M  = 50.31, SD  = 15.32) and years of education ranged from 2 to 17 years ( M  = 9.02, SD  = 4.11). All participants completed the LAS-FNAME and a brief neuropsychological evaluation. We examined associations between age, education, and sex and performance on the LAS-FNAME. Internal consistency, convergent and discriminant validity were also assessed. Test-restest reliability was computed for a subset of participants ( n  = 32)., Results: LAS-FNAME exhibited moderate convergent validity with other memory measures (Free and Cued Selective Reminding Scale, r s =.465, p <.01; Wechsler Memory Scale III - Logical Memory Delayed Recall, r s =.479, p <.01). The subscales of the LAS-FNAME exhibited adequate internal consistency ( α =.825). Test-retest reliability analyses demonstrated consistency of scores over time. Normative data was stratified by age (<50, 50-65, >65) and low and high educational attainment (≤8 and >8 years of education, respectively)., Conclusions: The LAS-FNAME is a valid and reliable measure to assess memory in clinically normal, Spanish-speaking individuals from Colombia for clinical and research purposes.

Objective: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories., Methods: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline., Results: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). β-amyloid (Aβ)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04)., Interpretation: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932., (© 2020 American Neurological Association.)

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., Competing Interests: Gad A. Marshall has received research salary support from Eisai Inc., Eli Lilly and Company, Janssen Alzheimer Immunotherapy, Novartis, and Genentech, and consulting fees from Grifols Shared Services North America, Inc.; Eisai Inc.; and Pfizer. Sietske A. M. Sikkes has received research support from Janssen, Axon Neuroscience, and Genentech and has received consulting fees from Boehringer and Toyama. Rebecca E. Amariglio has received research salary support from Eisai Inc., Eli Lilly and Company, and Biogen. Jennifer R. Gatchel has received research support from Merck. Dorene M. Rentz has received research salary support from Eli Lilly and Company and has received consulting fees from Eli Lilly, Neurotrack, and Lundbeck. Keith A. Johnson has received consulting fees from Novartis, Genentech, Biogen, AC Immune, Merck, Roche, Takeda, and Janssen. Oliver Langford reports no conflicts of interest. Chung‐Kai Sun reports no conflicts of interest. Michael C. Donohue has received research support from Eli Lilly and Company, Alzheimer's Association, and consulting fees from Eli Lilly and Company, Neurotrack, Biogen, and Roche. Rema Raman has received research salary support from Eli Lilly and Company and Janssen. Paul S. Aisen has received research support from Eisai Inc., Eli Lilly and Company, and Janssen, and has received consulting fees Biogen, Merck, Roche, Lundbeck, and ImmunoBrain Checkpoint. Reisa A. Sperling has received research support from Eli Lilly and Company and Janssen and has received consulting fees from AC Immune, Biogen, Eisai Inc., Janssen, Roche, and Takeda. Douglas R. Galasko has received research salary support from Eli Lilly and Company and Biogen, and consulting fees from vTv Pharmaceuticals, Cognition Therapeutics, and Fujirebio., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with "instrumental activities of daily living" (IADL) seem to increase gradually over the course of Alzheimer's disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD., Methods: In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging-Alzheimer's Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized., Results: The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = - 0.32 [- 0.55, - 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (- 1.06 [- 1.27, - 0.85], p < .001) and nearly two SD units per year in stage 4+ (1.93 [- 2.19, - 1.67], p < .001). Overall, results were similar between community-based and memory clinic study cohorts., Conclusions: Our results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results imply that incremental changes in function are a meaningful measure for early disease monitoring. Combined with the low-cost assessment, this advocates the use of these functional questionnaires for capturing the effects of early AD-related cognitive decline on daily life.

Background: To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer's disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers., Methods: A total of 35 cognitively intact mutation carriers (age range 26-41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27-44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation., Results: Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = - .436, p = .018) and regional tau in the entorhinal (r = - .394, p = .031) and inferior temporal cortex (r = - .563, p = .001) were associated with lower LAS-FNAME Total Scores., Conclusions: Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.

Objective: To identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD)., Methods: A total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education., Results: Neocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden., Conclusions: The presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions., (© 2020 American Academy of Neurology.)

Introduction: Demonstrating the "clinical meaningfulness" of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid-β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression., Methods: Cox regression analyses were used to determine whether 3-year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative., Results: Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta-analytic estimates were 5.47 (95% CI: 3.25-9.18) for MCI diagnosis and 4.49 (95% CI: 2.84-7.09) for Clinical Dementia Rating>0 in those with subtle decline (>-.14 to -.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing., Discussion: Early "subtle cognitive decline" among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment., (© 2019 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

A growing awareness about brain health and Alzheimer's disease in the general population is leading to an increasing number of cognitively unimpaired individuals, who are concerned that they have reduced cognitive function, to approach the medical system for help. The term subjective cognitive decline (SCD) was conceived in 2014 to describe this condition. Epidemiological data provide evidence that the risk for mild cognitive impairment and dementia is increased in individuals with SCD. However, the majority of individuals with SCD will not show progressive cognitive decline. An individually tailored diagnostic process might be reasonable to identify or exclude underlying medical conditions in an individual with SCD who actively seeks medical help. An increasing number of studies are investigating the link between SCD and the very early stages of Alzheimer's disease and other neurodegenerative diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To identify a parsimonious set of markers that optimally predicts subsequent clinical progression from normal to mild cognitive impairment (MCI)., Methods: 250 clinically normal adults (mean age = 73.6 years, SD = 6.0) from the Harvard Aging Brain Study were assessed at baseline on a wide set of markers, including magnetic resonance imaging markers of gray matter thickness and volume, white matter lesions, fractional anisotropy, resting state functional connectivity, positron emission tomography markers of glucose metabolism and β-amyloid (Aβ) burden, and a measure of vascular risk. Participants were also tested annually on a battery of clinical and cognitive tests (median follow-up = 5.0 years, SD = 1.66). We applied least absolute shrinkage and selection operator (LASSO) Cox models to determine the minimum set of non-redundant markers that predicts subsequent clinical progression from normal to MCI, adjusting for age, sex, and education., Results: 23 participants (9.2%) progressed to MCI over the study period (mean years of follow-up to diagnosis = 3.96, SD = 1.89). Progression was predicted by several brain markers, including reduced entorhinal thickness (hazard ratio, HR = 1.73), greater Aβ burden (HR = 1.58), lower default network connectivity (HR = 1.42), and smaller hippocampal volume (HR = 1.30). When cognitive test scores were added to the model, the aforementioned neuroimaging markers remained significant and lower striatum volume as well as lower scores on baseline memory and processing speed tests additionally contributed to progression., Conclusion: Among a large set of brain, vascular and cognitive markers, a subset of markers independently predicted progression from normal to MCI. These markers may enhance risk stratification by identifying clinically normal individuals who are most likely to develop clinical symptoms and would likely benefit most from therapeutic intervention., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences., Objective: To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline., Methods: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5)., Results: Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β  = -0.055, p = 0.025) after adjusting for covariates., Conclusion: Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

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, APOE ε4, sex, and age., Results: SCD increased odds of Aβ+ by 1.58 relative to non-SCD. Female APOE ε4 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 APOE ε4 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., (© 2019 The Authors.)

Importance: Depressive symptoms are prevalent among older adults and may be early manifestations of Alzheimer disease (AD) before onset of mild cognitive impairment. However, it remains unclear whether worsening depressive symptoms in the presence of AD pathology are associated with cognitive decline in older adults., Objective: To determine the longitudinal association between depressive symptoms, cognition, and cortical amyloid in community-dwelling older adults., Design, Setting, and Participants: Participants from the Harvard Aging Brain Study, a cohort study, underwent annual assessments of depression and cognition and baseline cortical amyloid measurement (mean, 4.42 years; range, 2-7 years). Data collection was from September 2010 to August 2017 in a convenience sample of community-dwelling adults (276 participants, all cognitively unimpaired) with at most mild depression at entry., Main Outcomes and Measures: Depression (Geriatric Depression Scale [GDS]), cognition (Preclinical Alzheimer Cognitive Composite [PACC]), and a continuous measure of cortical amyloid (Pittsburgh Compound-B positron emission tomography imaging). Change in GDS and baseline amyloid were examined as interactive predictors of PACC decline in a linear mixed model with backward elimination, adjusting for age, sex, and education., Results: Participants were 164 women and 112 men (mean [SD] age, 73.5 [6.0] years). At baseline, the mean (SD) GDS score was 3.0 (2.8) (range, 0-12), the mean (SD) PACC score was -0.004 (0.67) (range, -2.32 to 1.88), and the mean (SD) amyloid positron emission tomography distribution volume ratio was 1.16 (0.20) (range, 0.92-1.94). At last follow-up, the mean (SD) GDS score was 3.9 (2.9) (range, 0-12), and the mean (SD) PACC score was -0.09 (1.27) (range, -5.66 to 1.67). The interaction between cortical amyloid and increasing GDS was associated with declining cognition (β = -0.19; 95% CI, -0.27 to -0.12; P < .001)., Conclusions and Relevance: In this study, cortical amyloid moderated the association between worsening depressive symptoms and declining cognition in older adults. While future work is needed to better understand causal associations, these findings may enhance early detection and prevention of AD clinical symptoms.

Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals., Objective: To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET)., Design, Setting and Participants: This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET., Main Outcomes and Measures: A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined., Results: The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07)., Conclusions and Relevance: Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Objectives: Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated., Methods: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ ( 11 C-Pittsburgh compound B) and tau ( 18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites., Results: Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies., Interpretation: Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1-3 ANN NEUROL 2019;85:181-193., (© 2018 American Neurological Association.)

Background: A decline in instrumental activities of daily living (IADL) correlates with the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia and has been associated with frontal and parietal hypometabolism, lower cerebrospinal fluid amyloid β 1-42 , and inferior temporal cortical thinning. Identifying the underlying biomarkers of functional decline will allow for the early identification of individuals at risk of disease progression., Objective: To investigate the association between IADL impairment and in vivo regional cerebral tau and cortical amyloid deposition across clinically normal (CN) elderly, MCI, and AD dementia., Methods: Fifty-one CN elderly, 30 MCI, and 9 AD dementia participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent assessment of regional tau deposition with flortaucipir (FTP) positron emission tomography (PET). An aggregate of cortical amyloid burden was assessed by florbetapir PET. IADL were assessed using the Functional Activities Questionnaire (FAQ). Tau regions with unadjusted correlations of p ≤ 0.006 (Bonferroni correction) with FAQ were used to evaluate the cross-sectional association between FAQ (dependent variable) and regional cerebral tau deposition, amyloid burden, and tau-amyloid interaction in separate general linear regression models with backward elimination. Covariates included age, American National Adult Reading Test (AMNART) intelligence quotient (IQ), and Rey Auditory Verbal Learning Test (RAVLT) total learning., Results: Unadjusted correlations between FAQ and tau in the entorhinal cortex (EC) and inferior temporal cortex (IT) survived Bonferroni correction. FAQ was associated with the tau-amyloid interaction, such that in participants with greater amyloid burden, greater IADL impairment was associated with greater regional tau (EC tau × amyloid: partial r (pr) = 0.47, p < 0.001; IT tau × amyloid: pr = 0.54, p < 0.001). Significant associations were found when these regression models were repeated in symptomatic participants alone but not among CN participants., Conclusions: Greater medial and inferior temporal tau and cortical amyloid burden were associated with greater IADL impairment in AD. Further elucidation of the biomarkers underlying the functional decline will allow for the early identification of individual at risk of disease progression.

Background: Impairment in instrumental activities of daily living (IADL) may occur in the earliest stages of mild cognitive impairment (MCI). However, there are few reliable measures of IADL in MCI or that have a sufficient range of scores in clinically normal (CN) elderly. The objective of this pilot study was to examine the convergent validity of a phone performance-based IADL instrument, the Harvard Automated Phone Task (APT), designed to measure the earliest IADL changes in Alzheimer's disease (AD), with other sensitive performance-based and subjective measures of everyday functional capacity among CN and MCI participants., Methods: Twenty-nine CN and 17 MCI participants were administered the Harvard APT, the computer performance-based Czaja Functional Assessment Battery (CFAB), and the AD Cooperative Study ADL prevention instrument (ADCS ADL-PI) participant and study partner versions; in addition, 52 different CN and 7 MCI participants were administered the Harvard APT and the Subjective Study Partner and Participant-reported (SSPP) IADL scale. The Harvard APT was compared with the three other IADL assessments., Results: In both CN and MCI, better performance on the Harvard APT was associated with better performance on the CFAB. In CN, better performance on the Harvard APT was associated with better ADCS ADL-PI participant-reported IADL, while in MCI better performance on the Harvard APT was associated with better ADCS ADL-PI study partner-reported IADL. Furthermore, in CN better performance on the Harvard APT was associated with better SSPP-IADL participant and study partner-reported IADL., Conclusions: In this small pilot study, the Harvard APT, a brief, self-administered, objective measure of IADL performance, appears to correlate well with other sensitive measures of everyday functioning, providing good preliminary convergent validity for this new measure. Moreover, it appears to perform well across both CN and MCI participants, which suggests that it is a promising measure of early, clinically meaningful functional change. This may not be the case as suggested in our small sample for subjective IADL scales that may perform differentially depending on the reporter (self vs. study partner) across the clinical spectrum possibly due to diminishing awareness of IADL difficulties in individuals who become cognitively impaired. Secondary prevention trials in AD have a great need for such ecologically valid and reliable measures of early IADL changes.

Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined., Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults., Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis., Results: rs3846455G was associated with greater PACC decline (β= -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= -57.3 mm3/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0×10-4, p = 0.039)., Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.