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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.

BackgroundImpairment 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.MethodsIn 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.ResultsThe 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

Remote, digital cognitive testing on an individual's own device provides the opportunity to deploy previously understudied but promising cognitive paradigms in preclinical Alzheimer's disease (AD). The Boston Remote Assessment for NeuroCognitive Health (BRANCH) captures a personalized learning curve for the same information presented over seven consecutive days. Here, we examined BRANCH multi-day learning curves (MDLCs) in 167 cognitively unimpaired older adults (age = 74.3 ± 7.5, 63% female) with different amyloid-β (A) and tau (T) biomarker profiles on positron emission tomography. MDLC scores decreased across ascending biomarker groups, with the A + T- group performing numerically worse (β = –0.24, 95%CI[–0.55,0.07], p = 0.128) and the A + T+ group performing significantly worse (β = –0.58, 95%CI[–1.06,–0.10], p = 0.018) than the A-T- group. Further, lower MDLC scores were associated with greater cortical thinning (β = 0.18, 95%CI[0.04,0.34], p = 0.013). Our results suggest that diminished MDLCs track with advanced AD pathophysiology, and demonstrate how a digital multi-day learning paradigm can provide novel insights about cognitive decline during preclinical AD. [ABSTRACT FROM AUTHOR]

Background: In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b‐amyloid (Ab) is proposed as stage 2 of Alzheimer's disease (AD) by the NIA‐AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden. Methods: The present study includes cross‐sectional data from 9 independent cohorts with a total of 7217 CU older adults (57% female), aged 69.34 (1.20) years, recruited from general and memory‐clinic populations. Ab and tau biomarkers were measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Using established cut‐offs, 28% of participants were Aβ+, and 12% were Aβ+T+ (approximately one‐third of the sample had available tau data). We examined four SCD‐plus criteria as well as the mean number of SCD criteria met (i.e., mean SCD‐severity) in relation to both biomarker status and levels in logistic/linear regressions adjusted for age and sex for each cohort. Summary statistics were extracted for meta‐analyses. Results: The overall frequency of stage 2 AD varied from 7‐16% [4‐26%] according to each SCD‐plus criterion endorsement. Only 1‐5% [0‐8%] of participants meeting the SCD‐plus criteria also had both high Aβ and tau burden (Fig.1). The presence of self‐reported memory decline (SMD), an associated concern/worry, and a higher mean SCD‐severity were each associated with high Ab (status and continuous). Only the latter was associated with high tau status (Fig.2). Onset of SCD within the last 5 years, and feeling of worse performance than same‐age peers, were not associated with AD biomarkers at a Bonferroni‐corrected threshold. Conclusions: Our results suggest that widespread endorsement of multiple SCD features is more powerful than a single criterion alone in identifying both Aβ and tau in CU older adults. We found that the isolated SCD criterion was particularly sensitive to elevated Aβ, even after adjustment for tau, supporting the power of SCD as a very early behavioral marker of preclinical AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Orientation in time, space, and person is often impaired in Alzheimer's disease dementia. Subtle changes in orientation may occur in prodromal and preclinical disease stages. Here we aim to assess the cross‐sectional association between individuals' orientation to their own world, as measured with a novel AI‐based paradigm, and Alzheimer's disease biomarkers (amyloid and tau) in cognitively unimpaired older adults. Methods: Using an automated chatbot, 51 participants (74.2 ± 5.3 years, 57% female) provided details about personal memories and relationships (orientation in person), as well as recognition of dates of historical events (orientation in time) and geographical locations (orientation in space). Then, they answered ten questions for each of the three domains of orientation. Orientation accuracy was defined as the proportion of correct responses to these questions divided by the time taken to respond to all questions for each domain separately. All participants underwent Pittsburgh compound‐B (amyloid) and flortaucipir (tau) positron emission tomography (PET) scans. We analyzed the relationship between performance on the three orientation domains and the following PET regions of interests: global cortical amyloid and neocortical, medial temporal, retrosplenial, and precuneus tau. All models are adjusted for age, sex, and education. Results: Higher global amyloid burden was significantly associated with worse orientation in space, while interactions between amyloid and medial temporal and retrosplenial tau were significantly associated with orientation in time (see Table 1). Orientation in person was not associated with amyloid or tau. Figure 1 displays the relationship between orientation accuracy and amyloid for tertiles of medial temporal and retrosplenial tau. Conclusion: We found associations between orientation in space and time, but not person, and amyloid and tau, even in this small sample of individuals who were cognitively unimpaired, in agreement with previous work, which has shown that orientation in space and time deteriorates earlier in the course of Alzheimer's disease than orientation in person. These results suggest disorientation to be a core cognitive impairment along the Alzheimer's disease continuum and may infer a role for routine assessment of orientation, assessed using a personally tailored digital tool, in early diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

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 11CPittsburgh 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 [ABSTRACT FROM AUTHOR]